IncobotulinumtoxinA (Xeomin)
Manufacturer: Merz Pharmaceuticals, Greensboro, N.C.
Indications: IncobotulinumtoxinA is indicated for adults with cervical dystonia or blepharospasm. The drug is designed to decrease the severity of abnormal head position and neck pain in both botulinum toxin-naive and previously treated patients with dystonia and to relieve blepharospasm in adults who have previously used onabotulinumtoxinA (Botox).
Drug Class: The drug’s active ingredient is botulinum toxin type A, produced from the fermentation of Hall strain Clostridium botulinum serotype A. The botulinum toxin complex is purified from the culture supernatant; the active ingredient is then separated from the proteins (hemaglutinins and non-hemaglutinins) through a series of steps that yield the active neurotoxin. The molecular weight of Xeomin is 150 kD without the accessory proteins.
Uniqueness of Product: Xeomin blocks cholinergic transmission at the neuromuscular junction by inhibiting the release of acetylcholine from peripheral cholinergic nerve endings. This inhibition occurs according to the following sequence: neurotoxin binding to cholinergic nerve terminals, internalization of the neurotoxin into the nerve terminal, translocation of the light-chain part of the molecule into the cytosol of the nerve terminal, and enzymatic cleavage of SNAP25, a pre-synaptic target protein essential for the release of acetylcholine. Impulse transmission is re-established by the formation of new nerve endings.
Boxed Warning: The effects of incobotulinumtoxinA and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. Swallowing and breathing problems can be life-threatening, and deaths have been reported. Symptoms have been reported hours to weeks after injection.
The risk of developing symptoms is probably greatest in children who are treated for spasticity, but they can also occur in adults who are treated for spasticity and other conditions, particularly in patients with underlying conditions predisposing them to these symptoms. With unapproved uses of Xeomin, including spasticity in children and adults, and in approved indications, spread of effect has been reported at doses comparable to those used to treat cervical dystonia and at lower doses.
Warnings and Precautions:
Lack of interchangeability among botulinum toxin products. The potency units of Xeomin are specific to the preparation and the assay method used. They are not interchangeable with the other preparations of botulinum toxin products and, therefore, units of biological activity of Xeomin cannot be compared to or converted into units of any other botulinum toxin products assessed with any other assay method.
Spread of toxin effect. Postmarketing safety data suggest that botulinum toxin effects are sometimes observed beyond the injection site. Symptoms are consistent with the mechanism of action of the toxin and may include asthenia, muscle weakness, double or blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. Symptoms have occurred hours to weeks after the injection. Swallowing and breathing difficulties can be life-threatening, and fatalities related to the spread of toxin effects have occurred.
The risk of symptom development is probably highest in children who have been treated for spasticity, but symptoms can occur in adults treated for spasticity and other conditions, particularly patients with underlying conditions that would predispose them to these symptoms. In unapproved uses of the product (including spasticity in children and adults) and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia. Patients and caregivers should be advised to seek immediate medical care if swallowing, speech, or respiratory disorders occur.
Hypersensitivity reactions. Anaphylaxis, serum sickness, urticaria, soft-tissue edema, and dyspnea have been reported with botulinum toxin products. If serious or immediate hypersensitivity reactions occur, further injection of Xeomin should be discontinued and appropriate medical therapy should begin immediately.
Dysphagia and breathing difficulties in patients with cervical dystonia. Xeomin and other botulinum toxin products can result in swallowing or breathing problems. Patients with pre-existing swallowing or breathing problems may be more susceptible to these complications. In most cases, this effect is a consequence of weakening of muscles in the area of injection that are involved in breathing or swallowing. When distant effects occur, additional respiratory muscles may be involved.
Death as a complication of severe dysphagia has been reported after treatment with botulinum toxin. Dysphagia may persist for several months, and patients may require a feeding tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia, especially if swallowing or respiratory function is already compromised.
Treatment of cervical dystonia with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in critical loss of breathing capacity in patients with respiratory disorders who may have become dependent on these accessory muscles. Postmarketing reports mention serious breathing difficulties, including respiratory failure, in patients with cervical dystonia who received botulinum toxin products. Patients with a smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles tend to be at greater risk of dysphagia. In general, limiting the dose injected may decrease the occurrence of dysphagia.
Patients being treated with botulinum toxin may require immediate medical attention if swallowing, speech, or respiratory disorders develop. These reactions can occur within hours to weeks after the injection.
Pre-existing neuromuscular disorders. Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis (ALS), or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert–Eaton syndrome) should be monitored closely. Patients with neuromuscular disorders may be at an increased risk of clinically significant effects, including severe dysphagia and respiratory compromise from typical doses of Xeomin.
Ocular problems in patients with blepharospasm. Reduced blinking from injection of botulinum toxin products in the orbicularis muscle can lead to corneal exposure, persistent epithelial defects, and corneal ulceration, especially in patients with seventh cranial nerve disorders. The clinician should carefully test corneal sensation in eyes previously operated upon, avoid injection into the medial lower-lid area to avoid ectropion, and thoroughly treat any epithelial defect. Protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means may be needed.
Because of its anticholinergic effects, Xeomin should be used with caution in patients at risk for narrow-angle glaucoma.
Ecchymosis easily occurs in the soft tissues of the eyelid. Immediate gentle pressure at the injection site can limit that risk.
Human albumin and viral disease transmission. Xeomin contains albumin, a derivative of human blood. With effective donor screening and manufacturing processes, the risk of transmission of viral diseases is extremely remote, and a theoretical risk for transmission of Creutzfeldt–Jakob disease (CJD) is also considered remote. No cases of transmission of viral diseases or CJD have been reported for albumin.
Dosage: The potency units of Xeomin are specific to the preparation and assay method used, and they are not interchangeable with other preparations of botulinum toxin products. As a result, this drug’s units of biologic activity cannot be compared with or converted into units of any other botulinum toxin products assessed by any other assay method.
Cervical dystonia. The recommended initial total dose is 120 units. In a placebo-controlled trial using initial Xeomin doses of 120 units and 240 units, researchers noted no meaningful difference in the effectiveness of each dose. In previously treated patients, the clinician should consider the patient’s previous response to treatment, the duration of effect, and the adverse-event history when determining the dose.
Xeomin is usually injected into the sternocleidomastoid, levator scapulae, splenius capitis, scalenus, or trapezius muscle. This list is not exhaustive; any of the muscles responsible for controlling head position may require treatment. The dose and number of injection sites in each treated muscle should be tailored for each patient according to the number and location of the muscles to be treated, the degree of spasticity or dystonia, muscle mass, body weight, and responses to any previous botulinum toxin injections.
The frequency of repeated treatments should be determined by the patient’s clinical response, but injections generally should be given no more often than every 12 weeks.
Blepharospasm. The recommended initial total dose should be the same dose as the patient’s previous treatment with Botox, although responses to Xeomin and Botox may differ in individual patients. In a placebo-controlled trial in which patients received the same number of units as they had received previously with Botox, the mean dose per eye was about 33 units (range, 10–50 units), and the mean number of injections per eye was six. The maximum dose per eye in the controlled trials was 50 units (range, 10 to 50 units). In a controlled trial, few patients received a total dose above 75 units.
If the previous dose of Botox is not known, the initial dose of Xeomin should be between 1.25 and 2.5 units per injection site. The total initial dose of Xeomin in both eyes should not exceed 70 units (35 units per eye).
The number and location of injection sites should be based on the severity of blepharospasm and on the patient’s previous dose and response to Botox injections. Subsequent dosing should be adjusted for each patient, based on response, up to a maximum dose of 35 units per eye.
Xeomin dosing has not been established in patients with blepharospasm who have not been previously receiving Botox. The frequency of repeated treatments with Xeomin should be determined by the patient’s clinical response but generally should be no more often than every 12 weeks.
Administration. Reconstituted Xeomin is intended for intramuscular injection only. After reconstitution, the product should be used for only one injection session and for only one patient. Localization of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful. The number of injection sites depends on the size of the muscle to be treated and the volume of reconstituted product injected.
Commentary: According to an epidemiological study conducted in Rochester, Minnesota, focal dystonia (which includes cervical dystonia) and blepharospasm affect almost 295 people per million in the U.S. Dystonias can be disabling and painful and often interfere with daily activities.
The U.S. is the 20th country to approve Xeomin. More than 84,000 patients have been treated with Xeomin worldwide since 2005.
Xeomin is a botulinum toxin type A that is free from complexing proteins. In nature, C. botulinum produces the toxin in association with ancillary complexing proteins. Manufacturers use this naturally occurring protein complex to produce therapeutic botulinum toxin products. Merz, the manufacturer of Xeomin, uses a process that isolates the therapeutic component and eliminates these ancillary complexing proteins. Xeomin is a neurotoxin therapy and is formulated to yield the active neurotoxin with high specific biologic activity, a low molecular weight (150 kD), and a low bacterial protein load (hemagglutinins and non-hemagglutinins).
Sources: www.merzusa.com/pdf/Xeomin_PI.pdf; www.rehabpub.com; www.biospace.com, August 2, 2010
Ulipristal Acetate (Ella) Tablet
Manufacturer: Osny Pharma, Osny, France; León Farma S.A., León, Spain; Watson Pharma, Inc., Morristown, N.J. Under License From: Laboratoire HRA Pharma, Paris, France
Indication: Ulipristal acetate (ella) is a progesterone agonist/antagonist emergency contraceptive indicated for the prevention of pregnancy following unprotected sexual intercourse or a known or suspected contraceptive failure. The agent is not intended for routine use as a contraceptive.
Drug Class: Ella is designated chemically as 17α–acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3, 20-dione. The molecular weight is 475.6.
Uniqueness of Drug: When taken immediately before ovulation is to occur, ella results in the postponement of follicular rupture. The likely primary mechanism of action of ella for emergency contraception, therefore, is the inhibition or delay of ovulation; however, alterations to the endometrium that may affect implantation may also contribute to efficacy.
Warnings and Precautions:
Existing preganancy. This tablet is not indicated for the termination of an existing pregnancy. Pregnancy should be ruled out before ella is prescribed. If pregnancy cannot be excluded on the basis of the history or physical examination, pregnancy testing should be performed. A follow-up physical or pelvic examination is recommended if there is any doubt concerning the general health or pregnancy status of any woman after taking ella.
Ectopic pregnancy. A history of ectopic pregnancy is not a contraindication to the use of this emergency contraceptive method; however, health care providers should consider the possibility of an ectopic pregnancy in women who become pregnant or who complain of lower abdominal pain after taking ella. A follow-up physical or pelvic examination is recommended if there is any doubt concerning the patient’s health or pregnancy status after ella is taken.
Repeated use. The drug is intended for occasional use as an emergency contraceptive and should not replace a regular method of contraception. Repeated use of ella within the same menstrual cycle is not recommended, because the safety and efficacy of repeated use of the drug within the same cycle has not been evaluated.
Fertility following use. A rapid return of fertility is likely after treatment with ella for emergency contraception; therefore, routine contraception should be continued or initiated as soon as possible after ella is used to ensure ongoing prevention of pregnancy. Data on the use of ella with regular hormonal contraceptives are unavailable; however, as a result of the drug’s high affinity binding to the progesterone receptor, ella may reduce the contraceptive action of regular hormonal contraceptive methods. As a reliable barrier method of contraception, ella should be used with subsequent acts of intercourse that occur in the same menstrual cycle.
Effect on menstrual cycle. After ella intake, menses sometimes occur earlier or later than expected by a few days. In clinical trials, cycle length was increased by a mean of 2.5 days but returned to normal in the subsequent cycle. Seven percent of subjects reported menses occurring more than seven days earlier than expected, and 19% of participants reported a delay of more than seven days. If there is a delay in the onset of expected menses beyond one week, pregnancy should be ruled out.
Nine percent of women studied reported intermenstrual bleeding after they used ella.
Dosage and Administration: The recommended dose is one ella tablet taken orally as soon as possible within 120 hours (five days) after unprotected intercourse or a known or suspected contraceptive failure. The tablet can be taken with or without food. If vomiting occurs within three hours after the patient takes ella, repeating the dose should be considered. The tablet can be taken at any time during the menstrual cycle.
Commentary: About three million unintended pregnancies occur each year in the U.S., and just over half of these affect women who are using a regular method of contraception. Despite the many highly effective birth control options women have to choose from, no method is 100% perfect. Sometimes a backup birth control method is needed; sexual intercourse is also sometimes unplanned or, unfortunately, nonconsensual.
Ulipristal acetate (ella) represents a relatively new class of hormonal modulators; it blocks the action of the hormone progesterone. Progesterone gets its name from the fact that it is “pro-gestation;” it takes a back seat in a woman’s hormone cycle until right before, and then after, ovulation, when it is sent out by the site of the released egg in large amounts in order to protect the assumed pregnancy. Without progesterone, a pregnancy cannot continue. When the progesterone level surges, the body “assumes” that a pregnancy has occurred for about two weeks, until there is no message feedback from the pregnancy. Levels of progesterone (as well as those of other reproductive hormones) fall, triggering the menstrual period.
This compound has been shown to be safe and effective in reducing the risk of pregnancy for up to five days (120 hours) after unprotected intercourse or contraceptive failure. The blocking of progesterone makes implantation of the embryo impossible.
Source: www.accessdata.fda.gov/drugsatfda_docslabel/2010/022474s000lbl.pdf