Pocket Drug Guide

Posts Tagged ‘USA’

Drugs are listed in order of approval in the USA, from oldest to newest.

Felbamate

Felbamate is a broad-spectrum anti-epileptic drug. It is not considered to be a first-line drug because of its potential for serious idiosyncratic side-effects, including potentially fatal aplastic anaemia (incidence of 1 in 3000) and hepatic failure (incidence of 1 in 10000). Recent analyses indicate that aplastic anaemia and liver failure occur almost exclusively within the first year of therapy. During this period, safety monitoring consisting of liver function tests and blood counts is recommended with a frequency of up to twice monthly, despite lack of evidence that early detection of changes will prevent serious health problems, even if the drug is discontinued. Yet, felbamate may still be an important drug in the armamentarium for refractory patients, because it may control seizures when other drugs fail, and tends to be alerting rather than sedating. It has been found to be particularly effective in patients with Lennox-Gastaut syndrome. Felbamate should be started at 300-600 mg twice daily, and increased as necessary over several weeks, up to 3600 mg, or higher in some cases. Drug levels maybe useful, and serum concentrations of 30-80mg/1 are recommended. Three-times-a-day dosing may improve tolerability. Dose-related side-effects include insomnia, decreased appetite and weight loss, ataxia, Gastrointestinal upset and headache. Other serious idiosyncratic adverse events include rash and Stevens-Johnson syndrome. Felbamate has a complex metabolism and elimination, by both the hepatic and renal routes, and inhibits the metabolism of some drugs while inducing others. Adjustments in these medications may be necessary.

Lamotrigine

Lamotrigine is a broad-spectrum anti-epileptic drug that has been widely accepted as a first-line drug for both partial and generalized epilepsy syndromes. Clinical trials have supported its use in partial seizures, primary generalized tonic-clonic seizures, absence seizures and seizures associated with Lennox-Gastaut syndrome. There is some controversy regarding the use of lamotrigine in juvenile myoclonic epilepsy. It is commonly used, but may worsen myoclonus in some patients. Lamotrigine has been the subject of a number of head-to-head studies in newly diagnosed partial and generalized epilepsy. Lamotrigine was equally effective but better tolerated than phenytoin and carbamazepine in several somewhat under-powered studies. Several studies indicated that lamotrigine is better tolerated than carbamazepine in the elderly. A recent very large, randomized open-label study indicated that lamotrigine might be the drug of choice in patients with partial epilepsy, as it was equally effective but better tolerated, but in a companion study it was substantially less effective than valproate in patients with generalized or unclassified epilepsy. Some studies have advocated combining lamotrigine with valproate in refractory patients, to achieve maximum efficacy through a favourable pharmacodynamic interaction. However, side-effects are also enhanced when the drugs are combined. Initiation of lamotrigine is somewhat more complex than for other drugs. Slow titration is mandatory to reduce occurrence of serious rash. In monotherapy, initiation with 25mg/day for 2 weeks, then 50mg/day for another 2 weeks, followed by increases of 25-50 mg/week is appropriate. If the patient is receiving valproate at the time of initiation, starting doses and doses during titration should be cut in half, whereas if they are receiving enzyme-inducing anti-epileptic drugs such as phenytoin, carbamazepine or phenobarbital, doses can be doubled. Doses can then be increased as necessary. Typical doses for patients with newly diagnosed epilepsy are 100-200 mg/day. In refractory patients, doses may be as high as 500-1000 mg/day. There is a great deal of variability in serum concentrations that produce optimal effects. Some patients may do well at serum concentrations of 2mg/l, while others may need levels of up to 20 mg/1. Common dose-related side-effects of lamotrigine include mild tremor, double vision, headache and insomnia. Rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur. Risk is increased for children under 16, and is also more common with concomitant valproate use, and in patients who have experienced rash on other anti-epileptic drugs. Rash almost always occurs within the first 8 weeks of therapy. Other hypersensitivity reactions, although much rarer, may be seen, including lymphadenopathy, fever, hepatic or renal failure, disseminated intravascular coagulation and arthritis. Discontinuation of lamotrigine is recommended in the presence of rash or other indication of hypersensitivity, and it is very important to tell patients to call immediately with such symptoms. Rapid discontinuation can prevent a more severe, potentially life-threatening reaction. In the absence of any clinical symptoms of hypersensitivity, it is unclear that routine monitoring of liver function tests, blood counts or electrolytes is useful. Lamotrigine does not alter the metabolism of other drugs that are given concomitantly. However, other drugs may impact on the metabolism of lamotrigine. One important and common drug interaction that bears noting is that with oral contraceptives, which double the clearance and halve the half-life of lamotrigine. Women on lamotrigine should be told to notify their doctor of any changes in oral contraceptive pill use, something they might not otherwise think to do.

Gabapentin

Gabapentin is a narrow-spectrum drug. It is useful only in patients with partial epilepsy, that is those with simple or complex partial seizures, or partial-onset generalized tonic-clonic convulsions. Gabapentin is felt to be more useful in newly diagnosed patients with mild epilepsy and in the elderly, who benefit from the relatively mild side-effect profile and lack of drug interactions, but less useful in patients with refractory epilepsy. Although gabapentin can be initiated at a therapeutic dose of 1200-2400 mg/day, it appears to be better tolerated when titrated. Typically, 300 mg two times a day is well tolerated as a starting dose, but lower starting doses are needed in some patients. Clinical trials have only tested efficacy to 2400 mg/day. However, in clinical experience, higher doses can be useful. However, gabapentin displays dose-dependent, saturable absorption. At higher doses, less may be absorbed across the gut, leading to diminishing returns. The amount of absorption varies from person to person. Determining if serum levels are rising after dose increments can help ascertain whether increasing doses are futile. Gabapentin is not bound to plasma proteins, is eliminated renally and does not interfere with the metabolism of other medications, including anti-epileptic drugs or psychotropic agents. This makes it an ideal drug for the elderly and patients with chronic illness, who are likely to be taking other drugs. Common dose-related side-effects include somnolence, dizziness, ataxia and fatigue. Weight gain is also seen, and appears to be dose related. Peripheral oedema may occur in some patients. Occurrence of myoclonus has been reported, as well as occasional behavioural disturbance in children. There are no reports of serious idiosyncratic side-effects. Therefore, routine monitoring of liver function tests, blood counts and electrolytes is probably not warranted.

Topiramate

Topiramate is another anti-epileptic drug that is felt to be broad spectrum. It has been studied and found effective in patients with partial-onset or primary generalized tonic-clonic seizures, and in patients with seizures associated with Lennox-Gastaut syndrome. Topiramate is felt to be first-line therapy in all these conditions. One head-to-head study in newly diagnosed patients found topiramate to be equal in efficacy with valproate in patients with mostly generalized seizures, and with carbamazepine in patients with mostly partial seizures, although the study was under-powered and has been criticized methodologically. A recent open-label randomized study in newly diagnosed adults and children indicated that topiramate was as efficacious as any other drug for partial and generalized seizures, but was less well tolerated. However, the open-label nature of the study could have produced some bias. Topiramate should be started at a low dose and slowly titrated for best tolerability, although there are no safety concerns related to starting more rapidly. It is best tolerated when initiated at 25 mg/day and increased by 25 mg/week. Typical doses necessary for newly diagnosed patients are in the range of 100-200 mg, while, as is the case for most drugs, refractory patients may require much higher doses. Up to 1000 mg has been tested in clinical trials, although few can tolerate such high doses. As with lamotrigine, serum levels needed to achieve control are variable, from 2 to 20 mg/1. Monitoring serum levels may be useful. Topiramate is well absorbed and has minimal protein binding. Topiramate is partially metabolized by the liver and approximately 60% is excreted unchanged in the urine. The more common dose-related adverse events include somnolence, paraesthesias (especially of fingertips), fatigue, taste perversion, weight loss and dizziness. One of the side-effects that is relatively specific to topiramate is psychomotor slowing, which particularly affects speech. Patients may complain of word-finding difficulty or slowing of speech. Academic performance can be affected. This side-effect is significant in some patients, while others may escape it entirely, even at high doses. Potential, more serious side-effects that occur infrequently include nephrolithiasis, open-angle glaucoma, causing transient and reversible visual loss, and hypohidrosis in children. Rarely, the hypohidrosis has caused heat stroke with serious consequences. Children receiving topiramate have also rarely developed clinically significant metabolic acidosis. Milder forms are common. Topiramate has rarely been associated with hepatic failure, and this seems to happen more commonly when topiramate is combined with valproate. Topiramate does not impact the metabolism of most concomitant drugs, but it does raise phenytoin levels when added to patients with baseline higher phenytoin levels (e.g. above 15 mg/1), which can potentially cause phenytoin toxicity. Therefore, phenytoin levels should be monitored. In addition, the classic hepatic enzyme-inducing antiepileptic drugs, such as phenytoin and carbamazepine, will increase the metabolism of topiramate, and higher doses may be required.

Oxcarbazepine

Oxcarbazepine, an analogue of carbamazepine, is a narrow-spectrum drug that is considered to be a first-line therapy for the treatment of partial seizures. Although it is similar to carbamazepine, it is effective in some patients for whom carbamazepine has failed and is believed to have additional mechanisms of action. Oxcarbazepine is actually a prodrug for a mono-hydroxylated form, to which it is rapidly converted after oral administration. Several studies have been performed in patients with newly diagnosed epilepsy, comparing oxcarbazepine with older anti-epileptic drugs. In all of these studies, oxcarbazepine was equally efficacious. It was better tolerated than phenytoin and carbamazepine, and as well tolerated as valproate. Oxcarbazepine has been noted to exacerbate myoclonic seizures as well as absence.

Oxcarbazepine should be initiated with titration to avoid side-effects. However, in one inpatient study, 2400 mg/day was started, and caused few dropouts, thus rapid initiation in an emergency is possible. In outpatients, initiation of 300 mg twice daily and titration of 600mg/week is usually well tolerated. Effective doses range from 900 to 2400mg, but higher doses are not well tolerated in combination with other drugs, particularly those with similar side-effect profiles. If side-effects develop as the dose is being increased, spacing out dosing to three times daily, or even four times daily sometimes permits achievement of higher, more efficacious doses. Plasma concentrations of up to 45 mg/1 have been well tolerated. Frequent dose-related adverse events include somnolence, dizziness, headache, ataxia, nausea and vomiting, diplopia, blurred vision, vertigo and tremor. One problematic potential adverse event is hyponatraemia. In a recent study, hyponatraemia was substantially more common for oxcarbazepine (29.9%) than carbamazepine (35.5%), and serum sodium levels of <128mEqA occurred in 12.4%. Risk factors for hyponatraemia include older age and diuretic use. Hypersensitivity syndromes, including rash and Stevens-Johnson syndrome are rare consequences of oxcarbazepine use. Oxcarbazepine does not have the strong enzyme-inducing properties of carbamazepine, and also does not induce its own metabolism. Oxcarbazepine also acts as an inhibitor of phenytoin metabolism, and its own metabolism is induced by the classic inducing anti-epileptic drugs such as phenytoin and carbamazepine.

Tiagabine

Tiagabine is a drug that is considered second-line therapy, and is effective for partial seizures only. Like other drugs that work via y-aminobutyric acid enhancement, tiagabine may exacerbate absence and myoclonic seizures. Tiagabine was compared with carbamazepine in a study of newly diagnosed patients with partial seizures, and was found to be less efficacious. However, it was fairly effective as add-on therapy in patients with refractory epilepsy. Nonetheless, its use has waned in recent years. Of note, some reports of seizures have surfaced when tiagabine has been used off-label for psychiatric indications. Tiagabine is best tolerated when titrated. Initiation of 4 mg once or twice daily is recommended, with dose increments of 4mg/week. A three-four-times-a-day regimen is recommended, due to the short half-life. Doses of up to 64 mg have been used in add-on trials. Patients receiving enzyme inducers will need higher doses than patients taking non-inducing anti-epileptic drugs. Serum levels have not been very clinically useful, due to the short half-life, which results in wide fluctuations in levels from peak to trough. Tiagabine is 96% protein bound, but no protein-binding interactions have been identified clinically. Common dose-related side-effects include tiredness, nervousness, dizziness, headache, tremor and abnormal thinking. An unusual side-effect has been identified, consisting of a stuporous state accompanied by a slow wave or spike-wave pattern on electroencephalogram. This resolves promptly with discontinuation of the drug. Another atypical side-effect is described as weakness or asthenia. No metabolic, hepatic or blood-related adverse events have been identified. Therefore, monitoring of complete blood counts, electrolytes and liver function tests is not clinically warranted. Tiagabine does not impact on the metabolism of other drugs. Other anti-epileptic drugs can impact on the metabolism of tiagabine.

Levetiracetam

Levetiracetam is a broad-spectrum drug that has undergone extensive testing. Therefore, more syndromes have been explored than for some of the other newer anti-epileptic drugs. It is effective in partial seizures. A study of patients with newly diagnosed partial or generalized tonic-clonic seizures showed no differences in efficacy or tolerability between levetiracetam and carbamazepine. Levetiracetam is the only newer anti-epileptic drug approved for use in juvenile myoclonic epilepsy. It was also effective for idiopathic generalized tonic-clonic seizures in an add-on situation. Case series have indicated efficacy in other idiopathic epilepsy syndromes.

One reason levetiracetam has become a very popular choice, for both initial and add-on therapy, is that it is easy to use. It can be started at a therapeutic dose, and data indicate that onset of action is within a day. Patients can be started on either 500mg once daily or 500 mg twice daily. The dose can then be increased gradually as necessary, with maximal dose typically being 3000 mg/day. If necessary, it can be started at a higher dose, although it is not clear if this is clinically necessary. In one study, levetiracetam was started at 4000 mg/ day, and was well tolerated. Serum levels are typically within the range of 10—40mgA, but will vary substantially over the course of a day, because of the short half-life of the drug. Another advantage of levetiracetam is that it is associated with no drug interactions because it is predominantly renally excreted, and shows limited metabolism in humans. As with other renally excreted drugs, lower doses should be used in the elderly, because they have a reduced creatinine clearance .

Side-effects of levetiracetam include irritability, somnolence, dizziness, asthenia and headache. Other uncommon adverse events include behavioural problems, depression and psychosis. Levetiracetam does not often cause rash, and is therefore a reasonable choice in patients with a history of hypersensitivity syndrome. To date, there has been no indication that levetiracetam can cause idiosyncratic safety problems such as aplastic anaemia or hepatic failure. Therefore, routine monitoring of liver function tests, blood counts and electrolytes is not clinically warranted.

Levetiracetam was recently approved in an i.v. formulation. It is being used more frequently for inpatients with other medical conditions who require immediate anti-epileptic drug therapy, and in status epilepticus, but no formal studies have been done.

Zonisamide

Zonisamide is felt to be broad spectrum. Unfortunately, trials in generalized seizure syndromes have not been performed to confirm this clinical impression. The only randomized controlled trials were performed in adults with partial seizures. Randomized trials in patients with newly diagnosed epilepsy have also not been done. Case series and open studies support a role for zonisamide in the treatment of syndromes associated with myoclonus, including juvenile myoclonic epilepsy and progressive myoclonic epilepsies. Zonisamide is better tolerated when it is titrated at initiation. It can be started at 50mg/day or 100 mg/day. The dose should then be titrated by 50mg/week or 100 mg every other week. Doses of 200-300 mg are common, and up to 500 mg can be necessary in difficult-to-treat patients. Serum concentrations of 20-40 mg/1 are considered therapeutic. Since the half-life is long (up to 60 h), serum concentrations can be expected to be steady over the course of the day. Common dose-related adverse events include fatigue, weight loss, dizziness, somnolence, anorexia and abnormal thinking, and decreased sweating. Zonisamide has also been associated with idiosyncratic side-effects. These include hypersensitivity syndromes such as rash and Stevens-Johnson syndrome and renal calculi. Patients living in hot climates, who are on high doses and have a family history of renal calculi may be at higher risk. Patients receiving zonisamide should be advised to drink plenty of fluids. The recurrence rate, even if zonisamide is continued, is not 100%. Hypohidrosis has also been seen, again more common in hot climates, and may infrequently lead to heat stroke in children. Zonisamide is well absorbed and is not extensively bound to plasma proteins. Since enzyme-inducing drugs such as carbamazepine and phenytoin can significantly reduce the half-life of zonisamide, higher doses will be needed in patients taking them in combination. Zonisamide metabolism can also be inhibited by a number of medications as well as by grapefruit juice. Zonisamide has essentially no impact on the pharmacokinetic parameters of other drugs.

Pregabalin

Pregabalin has a similar efficacy profile to gabapentin, that is to say its use is restricted to partial seizures. No formal monotherapy studies have been completed, in either newly diagnosed or refractory patients. An advantage of pregabalin when compared to gabapentin, is that it is highly bioavailable, and does not require active dose-dependent transport in the Gastrointestinal tract. Pregabalin is better tolerated when titrated. A recent study indicated that starting at the highest dose of 600 mg, while safe, led to 32% dropouts. Pregabalin can be initiated at 50-75 mg twice daily, and titrated by 50-75 mg every week or two weeks. There are very few clinical data available regarding the safety and tolerability of doses above 600mg/day. Twice-daily dosing is commonly used, despite the short half-life of the drug. A study comparing efficacy and tolerability of the same total daily dose, given as twice daily or thrice daily showed no statistically significant difference, but there was a trend to both better efficacy and tolerability when thrice daily was used. Therefore, it is reasonable to start off with a twice-daily regimen, and switch to thrice daily only if side-effects are present and/or breakthrough seizures are occurring. Pregabalin levels have only recently become available, and their clinical utility is unknown. Common dose-related side-effects predominantly affecting the central nervous system include dizziness, somnolence and ataxia. Weight gain and peripheral oedema are also seen. Weight gain is also dose related. To date, no idiosyncratic side-effects have been identified. Need for routine monitoring of liver functions, electrolytes and blood counts is therefore not established. Pregabalin is almost exclusively excreted unchanged in the urine, and does not undergo metabolic changes. To date, no drug-drug interactions have been uncovered, and none are expected.

Vigabatrin (not approved in the usa)

Vigabatrin, like felbamate, is an anti-epileptic drug that has been associated with a significant adverse drug effect (irreversible visual field restriction) that limits its use to those patients who have severe epilepsy which has not responded to other anti-epileptic drugs. In adults, vigabatrin appears to have a narrow spectrum of action, and its use is primarily restricted to those patients with refractory partial epilepsy. It has been found inferior in efficacy to carbamazepine in trials of newly diagnosed patients. It has also been known to worsen myoclonus. In infants, however, vigabatrin was found to be highly effective in the devastating childhood epilepsy known as infantile spasms, or West syndrome [99]. In a randomized trial, there was a 78% reduction in seizures on vigabatrin, compared with 26% on placebo. Moreover, in the open-label phase, 38% of children were completely spasm free. Vigabatrin is particularly effective in patients with spasms associated with tuberous sclerosis. Vigabatrin can be initiated at 500-1000mg, given once or twice a day. The dose can be increased in 500-1000 mg weekly increments, up to 3000 mg. Some patients worsen at higher doses. Vigabatrin has unique pharmacokinetic properties, in that its mechanism of action involves changes in brain chemistry that far outlast its presence in the bloodstream. Therefore, vigabatrin levels are not useful for therapeutic monitoring.

As noted, the main safety concern relates to irreversible peripheral visual field defects. This problem is estimated to occur in 30-50% of patients receiving the drug. Often, this will be picked up on screening visual field testing, but the patients will not spontaneously report any problem. Since early development of this problem has not been seen in controlled studies, there may be a 3-month ‘window of opportunity’ to see if the drug works before there is a risk of the visual field defect. However, once it occurs, it is not reversible.

Other side-effects of vigabatrin include drowsiness, depression, weight gain, dizziness and rare psychosis .

Anticonceptivos hormonales; Contraceptifs Hormonaux; Hormonale Kontrazeptiva

Ectopic pregnancy. All methods of contraception effectively reduce the risk of ectopic pregnancy overall by reducing the rate of pregnancy. However, when contraception fails the proportion of pregnancies that are ectopic is higher for users of oral and in-tra-uterine progestogen-only contraceptives and levonorgestrel implants than in the general population. There is no increase in the proportion of ectopic pregnancies for methods that inhibit ovulation more reliably, such as combined oral contraceptives and medroxyprogesterone acetate depot injection.

A small number of cases of ectopic pregnancy after failure of emergency contraception, with both the Yuzpe regimen (oestrogen plus progestogen) and progestogen-only contraception, have been reported. However, data from clinical studies and postmarketing surveillance have shown that when levonorgestrel emergency contraception does rarely fail, there is no increase in the chance of ectopic pregnancy occurring.

Effects on body-weight. Weight gain has been reported as an adverse effect of combined oral contraceptives, but there is no strong evidence from clinical studies to confirm that they have a significant effect on weight. However, there is some evidence that weight gain might be associated with medroxyprogesterone acetate when given as a long-acting injectable contraceptive. There have been reports of both weight gain over 5 years, and no change in weight over 10 years, in women using medroxyprogesterone compared with those using a copper IUD. Studies in adolescents using medroxyprogesterone or an oral contraceptive for 12 or 18 months have reported more weight gain in those using medroxyprogesterone, and that significant weight gain was more likely in those who were overweight when contraception was started. The risk of weight gain, however, may be confounded by a number of factors including age, race, diet, exercise, and prior pregnancy.

For discussion of a possible association between obesity and oral contraceptive failure, see Obesity, under Precautions, below.

Effects on carbohydrate metabolism. The potential effects of oral contraceptives on carbohydrate metabolism are of concern because impaired glucose tolerance, hyperinsulinism, and insulin resistance contribute to atherogenesis and cardiovascular disease. Early studies suggested that the prevalence of abnormal glucose tolerance in oral contraceptive users was increased from about 4 to 35%. This decreased glucose tolerance was found to be related to oestrogen dose, particularly those greater than 75 micrograms daily, and to the type of progestogen. Marked hyperglycaemia has been associated with contraceptives containing high doses of oestrogen but is not seen with combined oral contraceptives used currently, which contain lower doses of oestrogen. Progestogens have little effect on glucose tolerance, but are associated with hyperinsulinaemia. This effect is dose-dependent, and levonorgestrel has the most potent effect, with desogestrel, gestodene, and norethisterone reported to have less effect. Combined oral contraceptives can also induce insulin resistance it is believed that the oestrogen is responsible and that the progestogen modifies this effect.

Despite evidence of these effects, more recent studies of lower-dose preparations containing desogestrel, levonorgestrel, or norethisterone have found little or no effect on various measurements of carbohydrate metabolism this lack of effect has also been confirmed in a meta-analysis of studies of hormonal contraceptive use in non-diabetic women although it was noted that no strong statement could be made since few studies compared the same types of contraceptives and some had large drop out rates. Also, data from the Nurses’ Health Study indicate that oral contraceptive use does not appear to increase the risk of developing type 2 diabetes mellitus. However, a study in the USA of breast-feeding women of Hispanic origin who had experienced recent gestational diabetes, suggested that the use of progestogen-only, but not combined, contraceptives was associated with an increased risk of developing type 2 diabetes mellitus in this group.

Injectable progestogen-only contraceptives have been reported in epidemiological studies to be associated with an increase in the incidence of type 2 diabetes mellitus. However, metabolic studies in lean, non-diabetic women have generally found no effect on glucose concentrations, suggesting that obesity or weight gain associated with injectable progestogen-only contraceptive use may play a role.

Drug Nomenclature

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

European Pharmacopoeia, 6th ed. (Norethisterone). A white or yellowish-white crystalline powder. Practically insoluble in water sparingly soluble in dehydrated alcohol and in acetone soluble in dichlorometh-ane.

The United States Pharmacopeia 31, 2008 (Norethindrone). A white to creamy-white odourless crystalline powder. Practically insoluble in water sparingly soluble in alcohol soluble in chloroform and in dioxan slightly soluble in ether.

Norethisterone Acetate

Drug Nomenclature

Pharmacopoeias. In Europe, International, and US.

European Pharmacopoeia, 6th ed. (Norethisterone Acetate). A white or yellowish-white crystalline powder. It exhibits polymorphism. Practically insoluble in water soluble in alcohol freely soluble in dichloromethane. Protect from light.

The United States Pharmacopeia 31, 2008 (Noneth in drone Acetate). A white to creamy-white odourless crystalline powder. Practically insoluble in water soluble 1 in 10 of alcohol, 1 in less than 1 of chloroform, 1 in 2 of dioxan, and 1 in 18 of ether.

Norethisterone Enantate

Drug Nomenclature

Pharmacopoeias. In International

Adverse Effects and Precautions

As for progestogens in general (see Progesterone). See also under Hormonal Contraceptives.

Effects on the liver. There were 6 cases of jaundice among 107 patients with breast cancer treated with high-dose norethisterone acetate the jaundice was reversible and of an obstructive type. A retrospective analysis found that the use of norethisterone to prevent menstrual haemorrhage during the thrombocytopenic phase of allogeneic bone marrow transplantation was a significant risk factor for hepatic veno-occlusive disease.

Porphyria. Norethisterone has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Pregnancy. Abnormalities seen in the offspring of women given norethisterone during pregnancy (either alone or with ethinylestradiol) included: hypospadias, masculinisation of female infants, meningomyelocele or hydrocephalus, and neonatal choreoathetosis associated with oral contraceptive use. For reference to the fact that oral contraceptives have not generally been associated with teratogenicity, even when used inadvertently in pregnancy.

Venous thromboembolism. For mention that combined oral contraceptives containing older progestogens such as norethisterone appear to be associated with a lower incidence of venous thromboembolism than desogestrel- or gestodene-containing preparations.

Interactions

As for progestogens in general (see Progesterone). See also under Hormonal Contraceptives.

Pharmacokinetics

Norethisterone is absorbed from the gastrointestinal tract, undergoing first-pass hepatic metabolism, with peak plasma concentrations occurring 1 to 2 hours after an oral dose. It exhibits biphasic pharmacokinetics an initial distribution phase is followed by a prolonged elimination phase with a half-life of about 8 hours or more. Norethisterone is highly protein bound about 60% to albumin and 35% to sex hormone binding globulin. Use with an oestrogen increases the proportion bound to sex hormone binding globulin. It is metabolised in the liver with 50 to 80% of a dose being excreted in the urine and up to 40% appearing in the faeces.

Norethisterone acetate is rapidly hydrolysed to norethisterone, principally by intestinal tissue. After intramuscular injection of norethisterone enantate peak concentrations of norethisterone in plasma are not attained for several days.

Uses and Administration

Norethisterone and its acetate and enantate esters are progestogens (see Progesterone) derived from nortestosterone that have weak oestrogenic and andro-genic properties. They are commonly used as hormonal contraceptives. Norethisterone and norethisterone acetate are both given orally. Typical daily doses are 350 micrograms for norethisterone and 600 micrograms for norethisterone acetate when used alone, or 0.5 to 1 mg for norethisterone and 1 to 1.5 mg for norethisterone acetate when used with an oestrogen. Norethisterone enantate is given by intramuscular injection a dose of 200 mg provides contraception for 8 weeks. An intramuscular injection containing norethisterone enantate 50 mg with estradiol valerate 5 mg is given once each month.

Norethisterone and norethisterone acetate are used as the progestogen component of menopauasl HRT. Typical regimens have included either continuous daily doses of norethisterone 700 micrograms or norethisterone acetate 0.5 to 1 mg, or cyclical regimens of norethisterone or norethisterone acetate 1 mg daily for 10 to 12 days of a 28-day cycle. Norethisterone acetate is also available as transdermal patches supplying 140, 170, or 250 micrograms in 24 hours, that are applied twice weekly for 2 weeks of a 4-week cycle the lower strengths may also be applied twice weekly on a continuous basis.

Norethisterone and norethisterone acetate may be given orally, usually in divided doses, for the treatment of conditions such as menorrhagia (below) and endometriosis. In menorrhagia (dysfunctional uterine bleeding), norethisterone is given in usual doses of 10 to 15 mg daily and norethisterone acetate in doses of 2.5 to 10 mg daily, in a cyclical regimen. In endometriosis the dosage of norethisterone is 10 to 25 mg daily and of norethisterone acetate 5 to 15 mg daily. Treatment of endometriosis is usually continuous for 4 to 9 months.

Norethisterone has been used in daily doses of up to 15 mg orally in a cyclical regimen in the treatment of premenstrual syndrome. In breast cancer oral doses of up to 60 mg daily of norethisterone have been used.

Administration in children. Although unlicensed in the UK for use in children, the BNFC does include norethisterone for the management of delayed puberty in girls. It is added after 12 to 24 months of oestrogen therapy to establish a menstrual cycle and maintain sexual maturation, in an oral dose of 5 mg once daily for the last 7 days of a 28-day cycle.

Menorrhagia. Although cyclical norethisterone has been widely used for menorrhagia, it is of limited efficacy during ovulatory cycles being most effective for anovulatory bleeding, which occurs in a minority of women with menorrhagia.

Preparations

British Pharmacopoeia 2008: Estradiol and Norethisterone Acetate Tablets; Estradiol and Norethisterone Tablets; Norethisterone Tablets

The United States Pharmacopeia 31, 2008: Estradiol and Norethindrone Acetate Tablets; Norethindrone Acetate and Ethinyl Estradiol Tablets; Norethindrone Acetate Tablets; Norethindrone and Ethinyl Estradiol Tablets; Norethindrone and Nestranol Tablets; Norethindrone Tablets.

Proprietary Preparations

Argentina: Ginediol Primolut-Nor Selectan

Australia: Locilan Nicronor Noriday Primolut N

Austria: Duokliman Nicronovum Primolut-Nor

Belgium: Primolut-Nor

Brazil: Nicronor Norestin Primolut-Nor

Canada: Nicronor Norlutate †

Chile: Primolut-Nor

Czech Republic: Primolut-Nor †

Denmark: Mini-Pe

Finland: Mini-Pill Primolut N Primolut-Nor

France: Milligynon Primolut-Nor

Germany: Gestakadin Noristerat Primolut-Nor Sovel †

Greece: Fortilut Primolut-Nor

Hong Kong: Norcolut Primolut N

Hungary: Norcolut

India: Cycloreg Noristerat Norlut Primolut N Styptin

Indonesia: Anore Norelut Primolut N Regumen

Ireland: Noriday Primolut N

Israel: Primolut-Nor

Italy: Primolut-Nor

Malaysia: Depocon Norcolut Noriday Noristerat Primolut N Sunolut Trisequens †

Mexico: Noristerat Primolut-Nor

The Netherlands: Primolut N

Norway: Conluclag Primolut N

New Zealand: Noriday Primolut N

Philippines: Noristerat Primolut N

Poland: Primolut-Nor

Portugal: Primolut-Nor

Russia: Primolut-Nor

South Africa: Nicronovum Nur-Isterate Primolut N

Singapore: Norcolut Noristerat Primolut N

Spain: Primolut-Nor

Sweden: Nini-Pe Primolut-Nor

Switzerland: Nicronovum Primolut N

Thailand: Noristerat Primolut N Steron

Turkey: Primolut N

UK: Nicronor Nicronor HPT † Noriday Noristerat Primolut N Utovlan

USA: Aygestin Jolivette Nor-QD Ortho Nicronor

Multi-ingredient

Argentina: Activelle Estalis Estalis Sequi Estracomb Estragest Evorel Conti Evorel Sequi Kliogest Nesigyna Trial Combi Trial Gest Trial Pack † Trisequens

Australia: Brevinor Estalis Continuous Estalis Sequi Estracombi Improvil Kliogest Kliovance Norimin Norinyl-1 Synphasic Trisequens

Austria: Activelle Estalis Estalis Sequens Estracomb Fem-HRT † Kliogest Nericomb Nerigest Novofem Ovysmen Perikliman Primosiston Trinovum Trisequens

Belgium: Activelle Estalis Estracombi Kliogest Minestril † Novofem Ovysmen Trinovum Trisequens

Brazil: Activelle Biofim † Ciclovulon Cliane Estalis Estalis SQ Estracomb † Estragest Gineane Ginedisc 50 Plusf Kliogest Negestran † Nericomb Nerigest Nesigyna Natifa Pro Noregyna Primosiston Suprema Systen Conti Systen Sequi Trinovum † Trisequens

Canada: Brevicon Estalis Estalis Sequi Estracomb FemHRT Loestrin 1.5/30 Ninestrin Ortho 0.5/35 Ortho 1/35 Ortho 7/7/7 Ortho-Novum 1/50 Select 1/35 Synphasic

Chile: Activelle Cliane Enadiol Neta Estracomb Estragest Ginefolin Kliogest Nesigyna Primosiston Trisequens

Czech Republic: Activelle Estalis Estalis Sequi Estrace Plus † Estrace-C † Estracomb † Estragest † Kliane Kliogest Nenophase † Non-Ovlon † Novofem Pausogest Sequidot Systen Conti Systen Sequi Triaklim Trinovum Trisequens

Denmark: Activelle Econ † Estracomb Evo-Conti Evo-Sequi Femanor Femasekvens Kliogest Novofem Ostranorm † Trinorm † Trinovum Trisekvens

Finland: Activelle Estalis Estalis Sekvens Estracomb † Evorel Conti Evorel Sequi Kliogest Nericomb Nerigest Novofem Trisekvens

France: Activelle Kliogest Niniphase Novofemme Ortho-Novum 1/35 Triella Trisequens

Germany: Activelle Clionara Conceplan N Estalis Sequi Estracomb † Estragest Eve Gynamon Kliogest N Nericomb Nerigest Non-Ovlon † Nora-ratiopharm † Novofem Ostro-Primolut † Ovysmen † Primosiston † Prosiston † Sequostat † Sinovula † Synphasec Trinovum Trisequens

Greece: Activelle † Estalis Estracomb TTS Kliogest Systen Conti Systen Sequi Trisequens

Hong Kong: Activelle Brevinor Estracomb Kliogest Norimin † Norinyl-1 Novofem Synphase † Trinovum † Trisequens

Hungary: Activelle Estracomb Estragest Kliogest Pausogest Triaklim Trisequens Tulita

Ireland: Activelle Brevinor Estalis Estalis Sequi Estracombi Estrapak † Evorel Conti Kliogest Novofem Trisequens

Israel: Activelle Evorel Conti Evorel Sequi Kliogest Neno-Net † Novofem Trisequens

Italy: Activelle Estalis Sequi Estracomb Kliogest Trisequens

Japan: Ortho 777

Malaysia: Activelle Kliogest †

Mexico: Cliane Estalis Estracomb Evorel Conti Nesigyna Norace Norinyl Nostidyn Ortho-Novum 1/35 Ortho-Novum †

The Netherlands: Activelle Estalis Estalis Sequi Estracomb Kliogest Nodicon Neocon Novofem Trinovum Trisequens

Norway: Activelle Estalis Estalis Sekvens Kliogest Novofem Synfase Trisekvens

New Zealand: Brevinor Cliane Estrapak † Kliogest Kliovance Norimin Norinyl-1 Synphasic Trisequens

Philippines: Kliogest Nicropil

Poland: Activelle Estalis Estalis Sequi Estracomb Kliogest Novofem Systen Conti Systen Sequi Trinovum Trisequens

Portugal: Activelle Estalis Estalis Sequi Estracomb Kliogest Novofem Trisequens

Russia: Non-Ovlon Pausogest Triaklim Trisequens

South Africa: Activelle Brevinor † Estracombi Estro-Pause N Evorel Conti Evorel Sequi Kliogest Norinyl-1/28 Novofem Trinovum Trisequens

Singapore: Activelle Estracomb Kliogest Trisequens

Spain: Absorlent Plus Activelle Duofemme Endomina Plus Estalis Estalis Sequi Estracomb Nerigest Nerigest Sequi Trisequens

Sweden: Activelle Estalis Estalis Sekvens Estracomb † Evorel Nicronor Femanor Femasekvens Kliogest Novofem Orthonett Novum Synfase Trinovum Trisekvens

Switzerland: Activelle Estalis Estalis Sequi Estracomb Estragest Kliogest N Nericomb Nerigest Novofem Ovysmen Primosiston Systen Conti Systen Sequi Trinovum Trisequens

Thailand: Activelle Anamai †

Turkey: Activelle Estracombi Kliogest Nesigyna Trisequens

UK: Binovum Brevinor Climagest Climesse Clinorette Elleste Duet Conti Elleste-Duet Estracombi Estrapak † Evorel Conti Evorel Pak † Evorel Sequi FemTab Continuous † Kliofem Kliovance Loestrin Norimin Norinyl-1 Novofem Nuvelle Continuous Ovysmen Synphase Trinovum Trisequens

USA: Activella Aranelle Balziva Brevicon CombiPatch Estrostep Fe Estrostep † Femcon Fe FemHRT Junel Fe Leena Loestrin Loestrin Fe Nodicon Necon 1/50 Necon 10/1 I Necon 0.5/35, 1/35 NEE 1/35 Norinyl I + 35 Norinyl I + 50 Ortho-Novum 1/35 Ortho-Novum 1/50 Ortho-Novum 10/11 Ortho-Novum 7/7/7 Ovcon 35 Ovcon 50 Tilia Fe Tri-Legest Tri-Norinyl Zenchent

Venezuela: Cliane Estracomb † Estragest Nesigyna Primosiston-F.

Drug Nomenclature

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Floxuridine). Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°. Protect from light.

Adverse Effects, Treatment, and Precautions

As for Fluorouracil. Adverse reactions after intra-arterial infusion often include local reactions, thromboembolic complications, and infection or bleeding at the catheter site, or blockage of the catheter. Erythema, stomatitis, and gastrointestinal disturbances are relatively common. There have also been signs of liver dysfunction.

Effects on the liver. Serious biliary toxicity has been reported in over half of all patients receiving hepatic arterial infusions of floxuridine, usually manifesting as sclerosing cholangitis or acalculous cholecystitis; as a result some surgeons routinely remove the gallbladder at the time of infusion pump implantation. Extrahepatic biliary stenosis with jaundice and cholestasis has also been described; the authors suggest that this could lead to intra-hepatic biliary damage from bile stasis and infection, recurrent cholangitis, and biliary sclerosis. Floxuridine infusions have also been associated with a case of fatal progressive cirrhosis of the liver in the absence of overt cholestasis. Pseudoaneurysms of the hepatic artery, leading to serious retroperitoneal or gastrointestinal bleeding, have also been described.

Interactions

As for Fluorouracil.

Pharmacokinetics

Floxuridine is poorly absorbed from the gastrointestinal tract and it is usually given by injection. Floxuridine is metabolised mainly in the liver to fluorouracil after rapid injection. When given by slow intra-arterial infusion, more of the drug is metabolised to floxuridine monophosphate (F-dUMP). It is excreted as carbon dioxide via the lungs; some is excreted, as unchanged drug and metabolites, in urine. Floxuridine crosses the blood-brain barrier to some extent and is found in CSF.

Uses and Administration

Floxuridine is an antineoplastic which acts as an antimetabolite, either by conversion to fluorouracil (after rapid injection), or, when given by slow intra-arterial infusion, partly via floxuridine monophosphate (F-dUMP), which produces greater inhibition of DNA synthesis.

Floxuridine is used in the palliative treatment of hepatic metastases of colorectal cancer — see Malignant Neoplasms of the Liver. It has been tried in some other solid neoplasms. Doses of 100 to 600 micrograms/kg daily are given by continuous hepatic arterial infusion, usually with the aid of an infusion pump, until toxicity occurs.

White cell and platelet counts should be carried out regularly during therapy and treatment should be stopped if the white cell count falls rapidly or if the white cell or platelet count falls below acceptable levels (see also Bone-marrow Depression), or if major adverse effects occur.

Preparations

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

Proprietary Preparations

USA: FUDR.

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

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

Adverse Effects, Treatment, and Precautions

For a general outline see Antineoplastics.

The most common adverse effects of bortezomib include haematological toxicities (especially transient thrombocytopenia), decreased appetite, gastrointestinal disturbances, peripheral neuropathy, fatigue, fever, dyspnoea, rash, and myalgia. Complete blood counts including platelet counts should be monitored and therapy withheld or given at reduced doses if necessary. Peripheral neuropathy may also be dose-limiting. Other common adverse effects include hyperglycaemia, hypokalaemia, insomnia, anxiety, confusion, depression, blurred vision, eye pain, dizziness, dysgeusia, tremor, epistaxis, cough, rhinorrhoea, pruritus, arthralgia, oedema, and orthostatic hypotension. Tumour lysis syndrome, hypersensitivity, and seizures have been reported. Tachycardia, arrhythmias, palpitations, angina pectoris, and myocardial infarction have occurred. Congestive heart failure may be exacerbated and pulmonary oedema has been reported. There have been rare reports of acute respiratory distress syndrome, some of them fatal.

Renal impairment is common in patients with multiple myeloma and acute renal failure has developed in patients on bortezomib. Licensed product information in the UK considers that patients with compromised renal function should be monitored, and dose reductions considered if needed although in the United States of America this is considered unnecessary. Hepatotoxicity which may be reversible, has included increases in liver enzyme values, hyperbilirubinaemia, and acute liver failure; bortezomib should be used with caution in hepatic impairment.

The impact of proteasome inhibition by bortezomib on disorders associated with protein accumulation such as amyloidosis is unknown and caution is advised in these patients.

Effects on the nervous system. Treatment with bortezomib is often associated with peripheral neuropathy, mainly sensory, although cases of motor neuropathy have been reported. Results from an analysis found that the peripheral neuropathy associated with bortezomib seemed to be cumulative and dose-related, and increased in prevalence through the first 5 treatment cycles. Prolonged bortezomib exposure beyond this time did not seem to increase the incidence or severity of neuropathy. Development of neuropathy appeared to be independent of the previous neuro-toxic therapy. In most patients, neuropathic pain resolved or improved after dose modification or upon completion of therapy.

Effects on the skin. In 3 studies of bortezomib in patients with non-Hodgkin’s lymphoma, 26 of 140 patients developed an erythematous maculopapular rash. Six patients underwent biopsy; all cases revealed a small vessel necrotising vasculitis. Although some patients had dosage reductions implemented or therapy interrupted upon development ofthe rash, others were treated continuously without dose reduction, with no apparent adverse clinical consequences. Infact, analysis ofthe data supported a strong relationship between bortezomib-associated cutaneous vasculitis and a positive clinical response in patient with non-Hodgkin’s lymphoma. A macular brown-red eruption developed in a patient at the site of bortezomib infusions; abundant venous flushing was given from the fourth infusion, and the eruption did not recur, although hyperpigmentation persisted for several months.

Interactions

Bortezomib is metabolised in the liver via the cytochrome P450 isoenzymes CYP3A4, CYP2C19, and CYP1A2; CYP2D6 and CYP2C9 are also thought to play minor roles. Consequently, patients should be monitored closely when bortezomib is used with other drugs that induce or inhibit these isoenzymes. Hypoglycaemia and hyperglycaemia have occurred in diabetic patients receiving oral antidiabetics who were given bortezomib. Caution may be required if bortezomib is used with drugs that are associated with peripheral neuropathy or hypotension.

Pharmacokinetics

After a single intravenous dose of bortezomib, plasma concentrations decline in a biphasic manner; a distribution phase with a half-life of less than 10 minutes is followed by a terminal elimination phase of about 5 to 15 hours. After multiple doses, clearance decreases and there is an increase in the terminal elimination phase. Protein binding has been reported to be over 80%. In-vitro studies indicate that bortezomib is primarily oxidatively metabolised via the cytochrome P450 isoenzymes CYP3A4, CYP2C19, and CYP1A2; minor metabolism via CYP2D6 and CYP2C9 also occurs. The major metabolic pathway is deboronation to inactive metabolites.

Uses and Administration

Bortezomib is an inhibitor of the 26S proteasome, a large protein complex in cells that is responsible for breaking down regulatory proteins of the cell cycle. Such inhibition disrupts tumour cell turnover and induces apoptosis. Bortezomib is used for the treatment of multiple myeloma in patients who have failed at least one previous therapy. In the United States of America (US and USA), it is also used similarly for mantle cell lymphoma in patients given at least one previous therapy. Bortezomib is given in initial doses of 1.3 mg/m intravenously on days 1, 4, 8, and 11 of a 21-day cycle. At least 72 hours should elapse between consecutive doses of bortezomib. In the UK, licensed product information recommends that patients with a confirmed complete response should receive 2 additional cycles of bortezomib, and that those who respond but do not achieve complete remission receive a total of 8 cycles. In the USA, extended therapy of more than 8 cycles may be given, either on the standard schedule recommended above, or on a maintenance schedule of one dose weekly for 4 weeks (days 1,8, 15, and 22 of a 35-day cycle).

The dose should be reduced, or treatment withdrawn, according to toxicity particularly when peripheral neuropathy, neuropathic pain, and haematological toxicity occur.

Proprietary Preparations

Argentina: Velcade;

Australia: Velcade;

Belgium: Velcade;

Canada: Velcade;

Chile: Velcade;

Czech Republic: Velcade;

Denmark: Velcade;

Finland: Velcade;

France: Velcade;

Germany; Velcade;

Greece: Velcade;

Hong Kong; Velcade;

Hungary: Velcade;

Indonesia: Velcade;

Israel: Velcade;

Italy: Velcade;

Malaysia: Velcade;

Mexico: Velcade;

The Netherlands: Velcade;

Norway: Velcade;

New Zealand: Velcade;

Philippines: Velcade;

Poland: Velcade;

Portugal: Velcade;

Russia: Velcade:

Singapore: Velcade;

Spain: Velcade;

Sweden: Velcade;

Switzerland: Velcade;

Thailand: Velcade;

United Kingdom (UK): Velcade;

United States of America (US and USA): Velcade;

Venezuela: Velcade.

(US Adopted Name, rINNM)

Drug Nomenclature

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

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

International and Japan also include Bleomycin Hydrochloride.

China, includes Bleomycin A5 Hydrochloride for Injection.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Bleomycin Sulphate). The sulfate of a mixture of glycopeptides obtained by the growth of Streptomyces verticillus or by any other means; the two principal components of the mixture are N-[3-(dimethylsulphonio)propyl]bleomycinamide (bleomycin A2) and N-[4-(carbamimidoylamino)butyl]bleomycina-mide (bleomycin B2). A white or yellowish-white, very hygroscopic powder. It loses not more than 3% of its weight when dried. Very soluble in water; slightly soluble in dehydrated alcohol; practically insoluble in acetone. A 0.5% solution in water has a pH of 4.5 to 6.0. Store in airtight containers at a temperature of 2° to 8°.

The United States Pharmacopeia 31, 2008 (Bleomycin Sulfate). The sulfate salt of a mixture of basic cytotoxic glycopeptides, produced by the growth of Streptomyces verticillus or produced by other means. It has a potency of not less than 1.5 units and not more than 2.0 units/mg. It contains between 55 and 70% of bleomycin A2 and between 25 and 32% of bleomycin B2; the content of bleomycin B4 is not more than 1 %. The combined percentage of bleomycin A2 and B2 is not less than 90%. A cream-coloured, amorphous powder. It loses not more than 6% of its weight when dried. Very soluble in water. A solution in water containing 10 units/mL has a pH of 4.5 to 6.0. Store in airtight containers.

Incompatibility. A loss of bleomycin activity was reported when bleomycin sulfate solutions were mixed with solutions of carbenicillin, cefazolin or cefalotin sodium, nafcillin sodium, benzylpenicillin sodium, methotrexate, mitomycin, hydrocortisone sodium succinate, aminophylline, ascorbic acid, or terbutaline. The interactions of bleomycin have been summarised as the chelation of divalent and trivalent cations (especially copper), inactivation by compounds containing sulfhydryl groups, and precipitation by hydrophobic anions; solutions of bleomycin should not be mixed with solutions of essential amino acids, riboflavin, dexamethasone, or furosemide.

Stability. Bleomycin sulfate solutions appear to be equally stable in plastic or glass, despite some earlier studies suggesting loss of potency in plastic. There is some evidence that bleomycin is more stable in sodium chloride 0.9% than glucose 5%, and sodium chloride 0.9% is the diluent recommended by the licensed product information. UK licensed product information states that bleomycin sulfate is chemically and physically stable, once reconstituted and diluted as directed, for 10 days when refrigerated at 2° to 8° and protected from light. From a microbiological point of view, solutions should be used immediately; storage for longer than 24 hours at 2° to 8° is not recommended, unless prepared under controlled and validated aseptic conditions.

Units

8910 units of bleomycin complex A2/B2 are contained in 5 mg of bleomycin complex in one ampoule of the first International Reference Preparation (1980). The European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 specifies a potency of not less than 1500 international units per mg, calculated with reference to the dried substance. These units differ from those used by the USP: Bleomycin Sulfate (The United States Pharmacopeia 31, 2008) contains 1.5 to 2.0 units of bleomycin in each mg. A change in the labelling of preparations in the UK, from units equivalent to those of the USP to international units in line with the Ph. Europe, resulted in an apparent but artefactual increase in UK doses by a factor of 1000.

In some countries doses were formerly described in terms of mg-potency, where 1 mg-potency corresponded to 1 unit. In the original preparation 1 mg-potency was equivalent to 1 mg-weight but improvements in purification of the product led to a situation in which ampoules labelled as containing 15 mg (i.e. 15 units) contained far fewer mg-weight of bleomycin.

Adverse Effects and Treatment

For a general outline see Antineoplastics.

The most frequent adverse effects with bleomycin involve the skin and mucous membranes and include rash, erythema, pruritus, vesiculation, hyperkeratosis, nail changes, alopecia, hyperpigmentation, striae, and stomatitis. Fever is also common, and acute anaphylac-toid reactions with hyperpyrexia and cardiorespiratory collapse have been reported in about 1% of patients with lymphoma. There is little depression of the bone marrow. Local reactions and thrombophlebitis may occur at the site of parenteral dosage. The most serious delayed effect is pulmonary toxicity; interstitial pneumonitis occurs in about 10% of patients and progresses to fibrosis and death in about 1% of patients treated with bleomycin. Pulmonary toxicity is more likely in elderly patients and those given total doses greater than 400 000 international units (400 USP units). It is also more likely in patients who have had previous radiotherapy to the chest.

Effects on the lungs. Pneumonitis induced by bleomycin can progress to fatal pulmonary fibrosis. The presentation is often delayed; clinical manifestations include non-productive cough, dyspnoea, and sometimes fever (see Effects on the Lungs). Pneumomediastinum has also been reported as an initial manifestation of fatal pulmonary toxicity due to bleomycin. Risk factors for toxicity include increased age, deteriorating renal function, and concurrent or previous radiotherapy. The reaction is dose-related, and maximum doses have been set (see Uses and Administration, below). Other factors that may be implicated include the regimen used, concomitant oxygen supplementation, smoking history, underlying lung disease, and growth factor support. For further details of some of these risk factors, see under Interactions, below. There is no standard treatment for bleomycin-induced pneumonitis. Bleomycin therapy is usually stopped, and corticosteroids may be given although strong evidence to support their use is lacking. There is some suggestion that giving bleomycin by intravenous infusion rather than bolus injection may reduce pulmonary toxicity.

Effects on the skin, hair, and nails. Permanent nail loss and nail loss followed by regrowth with dystrophy have been reported after intralesional injection of bleomycin for periungual warts. In 2 cases this was preceded by blistering and ulcera-tion, or swelling, severe pain, and a burning sensation. All 3 patients had received injections on one or two previous occasions when 2 patients had reported only mild pain. Other reported cutaneous adverse effects of bleomycin include flagellate erythema, Raynaud’s phenomenon, gangrene, fibrotic or sclerotic skin changes, hyperpigmentation, and neutrophilic eccrine hidradenitis (an inflammatory dermatosis with erythematous plaques and nodules, neutrophilic infiltrates of eccrine glands, and degeneration of eccrine cells). Acute generalised exanthe-matous pustulosis and alopecia have also been reported.

Effects on the vascular system. Although thromboembolic disorders and Raynaud’s syndrome have been associated with use of bleomycin in combination regimens, particularly with cisplatin and the vinca alkaloids or etoposide (see Effects on the Cardiovascular System) there is some evidence for an association of Raynaud’s syndrome with the use of bleomycin alone.

There have also been cases of Raynaud’s phenomenon reported after intralesional injection of bleomycin for treatment of warts on the hands and feet. See also Effects on the Skin, Hair, and Nails, above.

Precautions

For reference to the precautions necessary with antineoplastics.

Bleomycin should be used with caution in the elderly, in patients with renal impairment or pulmonary infection or pre-existing impairment of pulmonary function, and in those who have received radiotherapy, particularly to the thorax. Patients should undergo regular chest X-rays. If these show infiltrates, or if breathlessness occurs, bleomycin should be stopped. In view of the risk of an anaphylactoid reaction it has been suggested that patients with lymphomas should receive two test doses of 2000 international units (2 USP units) or less initially (but see Administration, below).

AIDS. Cutaneous adverse effects occurred in 12 of 50 patients being treated with bleomycin for AIDS-associated Kaposi’s sarcoma and increased in severity until bleomycin was withdrawn. Bleomycin should be stopped in people with AIDS if cutaneous adverse effects are seen, and rechallenge should be avoided. However, the incidence of adverse effects did not appear to be higher in these patients than in cancer patients, and patients with AIDS seem to be less sensitive to bleomycin than to antibacteri-als such as co-trimoxazole and penicillins.

Diving. Since the partial pressure of oxygen in the inspired air of a scuba diver increases with increasing depth, a theoretical possibility exists of a toxic [pulmonary] reaction to oxygen in bleomycin-treated patients who subsequently go diving, and such a risk would increase with the depth and duration of each dive. However, the risks associated with diving after uncomplicated bleomycin-based treatment have been questioned; the authors considered that resuming diving was acceptable 6 to 12 months after completing treatment with BEP (bleomycin, etoposide, and cisplatin), and recommended caution only in those who developed pulmonary function impairment when given bleomycin.

Handling and disposal. Urine produced for up to 72 hours after a dose of bleomycin should be handled wearing protective clothing.

Pregnancy. For a report of use of a bleomycin-containing chemotherapy regimen in a pregnant woman and subsequent adverse effects on the infant, see Pregnancy, under Cisplatin.

Interactions

For a general outline of antineoplastic drug interactions. There may be an increased risk of pulmonary toxicity in patients given bleomycin who receive oxygen, for example as part of a general anaesthetic procedure; a reduction in inspired oxygen concentration has been recommended.

Antineoplastics. Enhanced pulmonary toxicity, in some cases fatal, has been reported in patients given bleomycin and cisplatin, presumably because cisplatin-induced renal impairment led to a decrease in bleomycin elimination. It seems reasonable to assume that similar interactions might occur if bleomycin were given with other nephrotoxic agents. It has been suggested that apart from a decrease in bleomycin dosage if nephrotoxic ity occurs with such a combination, giving bleomycin by constant infusion rather than intermittent bolus might be less toxic: A study to investigate whether substitution of etoposide with gemcitabine would lead to a less leukaemogenic BEACOPP regimen was stopped early because of unexpectedly common pulmonary toxicity; one patient died. This toxicity was considered to be due to the use of gemcitabine with bleomycin.

Colony-stimulating factors. An increased incidence of pulmonary toxicity has been reported in patients receiving bleomycin as part of the AB VD regimen (with doxorubicin, vinblastine, and dacarbazine) who were given granulocyte colony-stimulating factor to alleviate neutropenia. Another case of rapidly developing and fatal pneumonitis in a patient given BEP (bleomycin, etoposide, and cisplatin) with granulocyte colony-stimulating factor has been reported.

Analyses of study data failed to show increased pulmonary toxicity when granulocyte colony-stimulating factor was added to bleomycin-containing regimens in patients with germ cell tumours or non-Hodgkin’s lymphomas. In a retrospective review of patients with Hodgkin’s lymphoma, however, use of bleomycin with granulocyte colony-stimulating factor was associated with a statistically significant increase of pulmonary toxicity.

Oxygen. Because bleomycin is thought to cause pulmonary toxicity partly by induction of free radicals, use with high concentrations of oxygen could be hazardous, and reductions in inspired oxygen concentration have been recommended by licensed product information where oxygen supplementation is unavoidable. Animal studies show an increased risk of mortality with use of bleomycin and oxygen, although data in humans are lacking. The need for oxygen restriction in bleomycin-treated patients has, however, been questioned.

Pharmacokinetics

Bleomycin is thought to be poorly absorbed from the gastrointestinal tract. Absorption is rapid after parenteral, intraperitoneal, or intrapleural use. Bioavailability is 100% and 70% after intramuscular and subcutaneous dosage, respectively. A bioavailability of 45% has been reported after intraperitoneal or intrapleural use. Plasma protein binding is low. Enzymic degradation of bleomycin occurs, primarily in plasma, the liver and other organs, and to a much lesser extent in skin and lungs. Elimination is biphasic: mean initial and terminal half-lives of 0.5 and 4 hours respectively have been reported after an intravenous bolus. Elimination may be more prolonged after continuous intravenous infusion and mean half-lives of 1.3 and 9 hours respectively have been reported. About two-thirds of a dose is excreted unchanged in the urine; the rate of excretion is determined by renal function. Drug concentrations in the CSF are low. Bleomycin crosses the placenta.

Uses and Administration

Bleomycin is an antineoplastic antibiotic that binds to DNA and causes strand scissions, and is probably most effective in the G2 and M phases of the cell cycle. It is widely used to treat malignant disease; particularly squamous cell carcinomas, including those of the cervix and external genitalia, oesophagus, skin, and head and neck; Hodgkin’s disease and other lymphomas; malignant neoplasms of the testis, and malignant effusions. It has also been tried in other malignancies, including carcinoma of the bladder, lung, and thyroid, and some sarcomas, including Kaposi’s sarcoma. Bleomycin is often used with other antineoplastics, notably with doxorubicin, vinblastine, and dacarbazine (ABVD) for Hodgkin’s disease, and with etoposide and cisplatin (BEP) in testicular tumours. Bleomycin is given as the sulfate by either the intramuscular, intravenous, or subcutaneous route. It may also be given intra-arterially or instilled intrapleurally or intraperitoneally If intramuscular injections are painful they may be given in a 1% solution of lidocaine.

Doses are calculated in terms of the base, and are given in units, but the units used for preparations in the UK, which were formerly equivalent to those of the USP, are now international units equivalent to those of the Ph. Europe (see Units, above). Since 1000 international units is equivalent to 1 USP unit, UK doses now appear to be 1000 times greater than those previously in use, or than those in use in the USA, and care is recommended in evaluating the literature.

In the UK the licensed dose as a single agent for squamous cell or testicular tumours is 15 000 international units (15 USP units) three times a week, or 30 000 international units twice a week, by intramuscular or intravenous injection, although in practice treatment of malignancy will generally be with combination regimens. This may be repeated, at usual intervals of 3 to 4 weeks, up to a total cumulative dose of 500 000 international units. The dose and total cumulative dose should be reduced in those over 60 years of age (see below). Doses should be adjusted according to tolerance, and may need to be adjusted as part of combination chemotherapy. Continuous intravenous infusion at a rate of 15 000 international units per 24 hours for up to 10 days or 30 000 international units per 24 hours for up to 5 days may also be used. In patients with lymphoma a dose of 15 000 international units once or twice weekly by intramuscular injection has been suggested, to a total dose of 225 000 international units. Again, dosage should be reduced in older patients and in combination regimens if necessary. In the treatment of malignant effusions a solution of 60 000 international units in 100 mL of sodium chloride 0.9% may be instilled into the affected serous cavity. Treatment may be repeated as necessary up to a total cumulative dose of 500 000 international units depending on the patient’s age. Local anaesthetics or analgesics are given con-comitantly

In the United States of America licensed doses for lymphomas as well as squamous cell and testicular neoplasms are 250 to 500 international units/kg (0.25 to 0.5 USP units/kg), or 10 000 to 20 000 international units/m (10 to 20 USP units/m), given once or twice weekly. In view of the risk of an anaphylactoid reaction it has been suggested that patients with lymphomas should receive two test doses of 2000 international units (2 USP units) or less initially (but see Administration, below). In patients with Hodgkin’s disease, once a 50% response has been achieved it may be maintained with 1000 international units (1 USP unit) of bleomycin daily, or 5000 international units (5 USP units) weekly. In the UK, licensed product information suggests that a total dose of 500 000 international units (500 USP units) should not be exceeded. Total cumulative dose should not exceed 300 000 international units in those aged 60 to 69 years, 200 000 international units in those 70 to 79, and 100 000 international units in those 80 and over; the weekly dose should be no more than 60 000, 30 000 and 15 000 international units respectively. In the USA the recommended maximum total dose is 400 000 international units (400 USP units); it is generally agreed that patients receiving 400 000 international units or more are at increased risk of pulmonary toxicity (see Adverse Effects, above).

Dosage should be reduced in patients with renal impairment (see below).

Bleomycin hydrochloride has also been given parenterally for malignant neoplasms, and bleomycin sulfate has been applied topically for the local treatment of skin tumours.

Administration. Although test doses have been suggested as a way of avoiding anaphylactoid reactions in patients with lymphoma being treated with bleomycin, a review of the literature concluded that the evidence did not support such a strategy, since the onset of the reaction was unpredictable, and not associated with any particular dose. It had also been suggested that reactions were less frequent with intramuscular rather than intravenous dosage, but evidence for this was conflicting. There is some suggestion that giving bleomycin by intravenous infusion rather than bolus injection in combination regimens may result in reduced pulmonary toxicity.

Administration in renal impairment. A significant portion of a dose of bleomycin is excreted largely unchanged in the urine, and dose reduction should be considered in patients with renal impairment. UK licensed product information suggests a 50% dose reduction when the serum creatinine concentration is between 20 and 40 micrograms/mL and further reduction for serum creatinine above this. US licensed product information gives the following proposed percentages of the initial dose, based on creatinine clearance (CC): • CC 5 to 10 mL/mmute: 40%

• CC 10 to 20 mL/mmute: 45%

• CC 20 to 30 mL/mmute: 55%

• CC 30 to 40 mL/mmute: 60%

• CC 40 to 50 mL/mmute: 70%

• CC 50 mL/mrnute and above: 100%)

Leucoplakia. Leucoplakia is used to describe a white patch or plaque in the mouth which cannot be otherwise characterised. Such lesions are of concern because they may be pre-malignant, and patients with evidence of dysplasia may be at higher risk of transformation (see also Malignant Neoplasms of the Head and Neck). Leucoplakia must be distinguished from other conditions such as candidiasis, lichen planus, and oral hairy leucoplakia which is associated with HIV infection. Leucoplakia is often associated with tobacco smoking, and smoking cessation can result in regression. Where active treatment is desirable, small and easily accessible lesions can be removed surgically or by laser therapy, although they may recur. For extensive patches or those in which surgery would be difficult, the treatments described include topical bleomycin 1 %, dissolved in dimethyl sulfoxide and applied for 5 minutes daily for 14 consecutive days. In a group of 19 patients with dysplastic leucoplakia, improvement in the appearance of lesions and histo-logical evidence of remission of the dysplasia occurred in the majority of patients. Sustained effects were also found on long-term follow-up for up to 10 years.

There have been reports of partial or complete remission of leu-coplakia in studies of vitamin A or betacarotene given orally long-term, but lesions have recurred when supplementation was stopped. Topical treatment with retinoids such as tretinoin or isotretinoin has also been tried, with similar results to those of oral vitamin A and retinoid treatments. A small open study has also suggested that topical calcipotriol may be effective. A systematic review of treatments for leucoplakia found that there were few controlled trials reported, and that although these treatments might be effective in the resolution of lesions, the rate of relapse was high, and there was no evidence that they prevent malignant transformation.

Malignant effusions. Bleomycin is used for the sclerotherapy of malignant pleural and pericardial effusions.

Malignant neoplasms. Bleomycin is used in regimens for the management of Hodgkin’s disease, non-Hodgkin’s lymphomas, including AIDS-related lymphomas, and for germ-cell tumours of the ovary and testis, as well as for some other malignancies including those ofthe head and neck, and Kaposi’s sarcoma.

Pneumothorax. In a patient with AIDS and pneumocystis pneumonia who developed pneumothorax, instillation of bleomycin into each pleural cavity was successful in resolving the pneumothorax after tetracycline sclerotherapy failed to do so.

Warts. A number of studies have examined the local use of bleomycin sulfate to treat severe or resistant warts ofthe common, plane, plantar, eponychial, and mosaic types, usually by intralesional injection. At the doses used, adverse effects, other than pain at the inj ection site, do not seem to be common; however, nail dystrophy and Raynaud’s phenomenon have been reported (see under Effects on the Nails and Effects on the Vascular System, under Adverse Effects, above). Bleomycin has also been applied as a pressure-sensitive adhesive tape, and various techniques for better intralesional use have been investigated.

Preparations

British Pharmacopoeia 2008: Bleomycin Injection;

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

Proprietary Preparations

Argentina: Bileco; Bleocris; Blocamicina; Cytorich;

Australia: Blenamax; Blenoxane;

Belgium: Bleomin;

Brazil: Blenoxane; Bonar; Tecnomicina;

Canada: Blenoxane;

Chile: Blexit; Nikableomicina; Oncobleocin;

Czech Republic: Bleocin;

Germany: Bleo-cell; Bleomedac;

Hong Kong: Bleocin;

Hungary: Bleocin;

India: Bleochem; Bleocin; Bleocip;

Indonesia: Blenamax; Bleocin;

Japan: Bleo-S Bleocin;

Malaysia: Blenamax; Bleocin;

Mexico: Blanoxan; Bleolem;

New Zealand: Blenoxane;

Philippines: Blenoxane; Bloicin-S;

Poland: Bleocin;

Portugal: Blio †;

Russia: Blenamax;

South Africa: Blenoxane; Bleolem;

Singapore: Bleocin;

Thailand: Bleo-S; Bleocin; Bleolem;

Turkey: Bleocin; Bleolem;

United Kingdom (UK): Bleo;

United States of America (US and USA): Blenoxane

(US Adopted Name, rINN)

Drug Nomenclature

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

Adverse Effects and Precautions

The adverse effects of azacitidine are generally similar to those seen with cytarabine. Hypokalaemia, dyspnoea, and bruising are common.

Pharmacokinetics

Azacitidine is rapidly absorbed after subcutaneous use; the bioavailability relative to intravenous use is about 89%. The mean plasma half-life after subcutaneous injection is about 40 minutes. Azacitidine and its metabolites are excreted primarily in the urine; about 50% and 85% is recovered after subcutaneous and intravenous dosing, respectively. The mean elimination half-life is about 4 hours after subcutaneous or intravenous use.

Uses and Administration

Azacitidine is an antimetabolite antineoplastic with general properties similar to those of cytarabine. It also inhibits cellular pyrimidine synthesis. Azacitidine is used in myelodys-plastic syndromes; it has also been used in the treatment of acute myeloid leukaemia.

For the treatment of myelodysplastic syndromes, azacitidine is given subcutaneously or intravenously in a dose of 75 mg/m daily for 7 days, in 4-week cycles. If there is no benefit after 2 cycles, and no toxicity other than nausea and vomiting has occurred, the dose may be increased to 100 mg/m daily. Treatment for at least 4 cycles is usually needed.

Azacitidine should be used with caution in renal impairment and doses adjusted accordingly (see below).

Administration in renal impairment. Adverse renal effects of azacitidine include abnormalities in renal-function tests, renal tubular acidosis, renal failure, and death. US licensed product information recommends that if serum-bicarbonate concentrations fall to below 20 mEq/litre, the dose of azacitidine should be halved for the next course. If there are rises in serum concentrations of urea or creatinine, the next cycle of azacitidine should be delayed until these return to normal or baseline, and the dose should be halved on the next treatment course.

Proprietary Preparations

USA: Vidaza

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Adverse Effects and Precautions

As for progestogens in general (see Progesterone). See also under Hormonal Contraceptives.

Breast feed ing. Etonogestrel was found in the breast milk of 42 women given a contraceptive etonogestrel implant. Over the 4-month study, compared with a group who used an intra-uterine non-hormonal device, etonogestrel did not affect the volume or composition of breast milk, or the growth of the breast-fed infants. At 3 years of age there was no difference in growth between these 2 groups of children.

Vaginal bleeding. Prolonged vaginal bleeding, lasting from 2 to 26 weeks, has been reported with the use of etonogestrel sub-dermal implants. Blood transfusion was needed in the management of one patient. Heavy bleeding has been described in 2 women after the implant had broken while in place.

Interactions

As for progestogens in general (see Progesterone). See also under Hormonal Contraceptives.

Pharmacokinetics

Etonogestrel is highly bound to plasma proteins about 32% is bound to sex hormone binding globulin and 66% to albumin. It is metabolised by the cytochrome P450 isoenzyme CYP3A4, and both metabolites and unchanged drug are excreted in the urine and faeces. The elimination half-life is about 25 to 30 hours. Etonogestrel is distributed into breast milk.

Uses and Administration

Etonogestrel, the active metabolite of desogestrel, is used as a hormonal contraceptive. A subdermal implant containing 68 mg of etonogestrel is used as a progestogenonly contraceptive that is effective for 3 years. Etonogestrel is also used as the progestogen component of a combined contraceptive delivered via a vaginal ring device. The ring releases an average of 120 micrograms daily of etonogestrel and 15 micrograms daily of ethinylestradiol and remains in the vagina for 3 weeks it is then removed for a one-week break after which a new ring is inserted.

Etonogestrel is under investigation as a male contraceptive, given orally or by implant, with testosterone implants or injections.

Preparations

Proprietary Preparations

Argentina: lmplanon

Australia:: Implanon

Austria: Implanon

Belgium: Implanon

Brazil: Implanon

Chile: Implanon

Czech Republic: Implanon

Denmark: Implanon

Finland: Implanon

France: Implanon

Germany: Implanon

Greece: Implanon

Hungary: Implanon

Indonesia: Implanon

Italy: Implanon

Malaysia: Implanon

Mexico: Implanon

Norway: Implanon

Portugal: Implanon

Singapore: Implanon

Spain: Implanon

Sweden: Implanon

Switzerland: Implanon

Thailand: Implanon

Turkey: Implanon

UK: Implanon

USA: Implanon

Venezuela: Implanon

Multi-ingredient

Australia: NuvaRing

Austria: NuvaRing

Belgium: NuvaRing

Brazil: NuvaRing

Canada: NuvaRing

Chile: NuvaRing

Czech Republic: NuvaRing

Denmark: NuvaRing

Finland: NuvaRing

France: NuvaRing

Germany: NuvaRing

Greece: NuvaRing

Hungary: NuvaRing

Italy: NuvaRing

Mexico: NuvaRing

The Netherlands: NuvaRing

Norway: NuvaRing

Portugal: NuvaRing

Russia: NuvaRing

Spain: NuvaRing

Sweden: NuvaRing

Switzerland: NuvaRing

USA: NuvaRing