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P T. 2010 December; 35(12): 691–693.
PMCID: PMC3008381

Pharmaceutical Approval Update

Marvin M. Goldenberg, PhD, RPh, MS

OnabotulinumtoxinA (Botox) for Injection In Chronic Migraine

Manufacturer: Allergan, Irvine, Calif.

Indication: OnabotulinumtoxinA for injection is indicated for the prophylaxis of headaches in adults with chronic migraine (defined as 15 headache days or more per month and lasting for four hours per day or longer). The drug’s safety and effectiveness in preventing episodic migraine (defined as 14 headache days or fewer per month) have not been established.

Biological Class: Sterile, vacuum-dried, purified botulinum toxin type A (Botox) is produced from the fermentation of Hall strain Clostridium botulinum type A. The product is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin and several accessory proteins. Botox is intended for intramuscular and intradermal use.

Uniqueness of Biological Product: Botox blocks neuromuscular transmission by binding to acceptor sites on motor or sympathetic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves synaptosomal-associated protein 25 (SNAP-25), which is integral to the successful docking and release of acetylcholine from vesicles located within nerve endings.

In patients who were observed for four to six months, Botox produced migraine relief when injected into the muscles of the brow, eyes, forehead, and the side and back of the head near the neck. When given intramuscularly at therapeutic doses, Botox produces partial chemical denervation of the muscle, resulting in a localized reduction in muscle activity. Additional effects included occasional muscle atrophy, axonal sprouting, and the development of extrajunctional acetylcholine receptors. Reinnervation of the muscle may occur, thus slowly reversing the muscle denervation that was produced.

Boxed Warning: Postmarketing reports indicate that the effects of Botox, as well as all botulinum toxin products, may spread from the area of injection to produce symptoms consistent with botulinum toxin (e.g., asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties). Symptoms have been reported hours to weeks after injection.

Swallowing and breathing difficulties can be life-threatening, and fatalities have been reported. The risk of symptoms is probably greatest in children who are treated for spasticity, but symptoms can also occur in adults treated for spasticity and other conditions, particularly if they have underlying conditions that predispose them to these symptoms. In unapproved uses, including spasticity in children, 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 products. The potency units of Botox are specific to the preparation and the assay method used; they are not interchangeable with other botulinum toxin products. The drug’s units of biological activity cannot be compared with or converted into units of any other botulinum toxin products assessed with other specific assay methods.

Spread of toxin effect. Botulinum toxin effects may sometimes occur beyond the site of local injection, as described in the boxed warning. No definitive serious adverse events have been related to distant spread of toxin effect with dermatological Botox when given at the approved labeled dose of 20 units for glabellar lines or at 100 units for severe primary axillary hyperhidrosis.

Hypersensitivity reactions. Serious or immediate hypersensitivity reactions have been reported. If a reaction occurs, further injections of Botox should be discontinued.

Pre-existing neuromuscular disorders. Patients with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis (ALS), or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert–Eaton syndrome) should be closely monitored during botulinum toxin therapy. Patients with neuromuscular disorders may be at an increased risk of clinically significant effects.

Pulmonary effects. Patients with compromised respiratory status who receive Botox injections for upper-limb spasticity should be monitored closely.

Human albumin and transmission of viral diseases. Botox contains albumin, a derivative of human blood. As a result of effective donor screening and product-manufacturing processes, this medication poses only an extremely remote risk for the transmission of viral diseases.

Dosage and Administration: Botox therapy for migraine generally involves a total of 31 injections in seven areas (forehead, temples, neck, shoulders, and back of the head). For treating chronic migraine, injections are given approximately every three months. The agent is supplied in single-use doses of 100 units and 200 units per vial. Before injection, each vacuum-dried vial is reconstituted with sterile, non-preserved 0.9% sodium chloride injection USP. The proper amount of diluent is drawn up in the appropriate-size syringe, and the diluent is slowly injected into the vial. The vial should be discarded if a vacuum does not cause the diluent to be pulled into the vial. The drug should be gently mixed with the saline by rotating the vial. The date and time of reconstitution should be recorded on the space on the label. Botox should be administered within 24 hours after reconstitution. During this time period, the reconstituted product should be refrigerated at 2° to 8°C (36° to 46°F).

Parenteral use. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration and whenever the solution and the container permit.

Chronic migraine. The recommended dilution is 200 units/4 mL or 100 units/2 mL, with a final concentration of 5 units per 0.1 mL. The recommended dose is 155 units administered intramuscularly with a sterile 30-gauge, 0.5-inch needle as 0.1-mL injections (5 units) at each site. Injections should be divided across seven head and neck muscle areas (forehead, temples, back of the head, neck, shoulders). The recommended schedule for re-treatment is every 12 weeks.

Commentary: Chronic migraine, defined as headache occurring 15 or more days per month and lasting four hours or more, involves the intense pulsing of throbbing pain in one area of the head. The pain can be accompanied by nausea, vomiting, and sensitivity to light and sound. OnabotulinumtoxinA (Botox) is approved for the treatment of chronic migraine, but it has not been shown to be effective for episodic migraine (intermittent headache attacks occurring 14 days or less each month).

For patients with chronic migraine, Botox is given approximately every three months as multiple injections around the head and neck in an effort to reduce future headache symptoms. Adverse events may include neck pain and headache. Although the product label includes a boxed warning indicating that symptoms similar to those of botulism can be life-threatening, no serious adverse events have been reported with the use of Botox at the recommended dose to treat chronic migraine and when used for other approved indications.


Dabigatran Etexilate Mesylate (Pradaxa)

Manufacturer: Boehringer Ingelheim, Ridgefield, Conn. Indication: Dabigatran is indicated for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Drug Class: Dabigatran is a direct thrombin inhibitor (DTI). Its chemical formula is b-alanine, N-[[2-[[[4-[[[(hexyl-oxy)carbonyl]amino]iminomethyl]phenyl]amino] methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The drug’s empirical formula is C34H41N7O5 • CH4O3S. The molecular weight is 723.86 (mesylate salt), 627.75 (free base). The 150-mg capsule for oral administration contains 172.95 mg of dabigatran etexilate mesylate, which is equivalent to 150 mg of dabigatran etexilate.

Uniqueness of Drug: Dabigatran and its acyl glucuronides are competitive DTIs. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, the inhibition of thrombin prevents the development of a thrombus. Both free and clot-bound thrombin and thrombin-induced platelet aggregation are inhibited by the active moieties.

Warnings and Precautions:

Risk of bleeding. Dabigatran increases the risk of significant and sometimes fatal bleeding. Risk factors for bleeding include labor and delivery and drugs that increase the risk of bleeding in general (e.g., antiplatelet agents, heparin, fibrinolytic therapy, and chronic use of nonsteroidal anti-inflammatory agents).

Temporary discontinuation of dabigatran. Discontinuing anticoagulants, including dabigatran, because of bleeding or scheduled surgery places patients at an increased risk of a stroke. Lapses in therapy should be avoided. If dabigatran must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

Effect of P-gp inducers and inhibitors. The concomitant use of dabigatran with permeability–glycoprotein (P-gp) inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. No dose adjustments are needed if patients are taking P-gp inhibitors such as ketoconazole (Nizoral, PriCara), verapamil (Calan, Pfizer), amiodarone (Cordarone, Wyeth/Pfizer), quinidine, or clarithromycin (Biaxin, Abbott). These recommendations do not pertain to other P-gp inhibitors.

Dosage and Administration:

Recommended dose. For patients with a creatinine clearance (CrCl) of 30 mL/minute or more, the recommended dose of dabigatran is 150 mg taken orally, twice daily, with or without food. For patients with a CrCl of 15 to 30 mL/minute, the recommended dose is 75 mg twice daily. Dosing recommendations for patients with a CrCl of less than 15 mL/minute or those receiving dialysis cannot be provided.

Capsules should be swallowed whole. Breaking, chewing, or emptying the contents of the capsule can result in increased exposure.

If a dose of dabigatran is not taken at the scheduled time, it should be taken as soon as possible on the same day. A missed dose should be skipped if it cannot be taken at least six hours before the next scheduled dose.

Switching from or to warfarin. Patients who are switching from warfarin (Coumadin, Bristol-Myers Squibb) to dabigatran should discontinue warfarin and should start dabigatran when the International Normalized Ratio (INR) is below 2.0. For patients switching from dabigatran to warfarin, the starting time of warfarin should be adjusted according to the CrCl.

Switching from or to parenteral anticoagulants. For patients currently receiving a parenteral anticoagulant, dabigatran should be started 0 to 2 hours before the time that the next dose of the parenteral drug was to have been given or at the time of discontinuation of a continuously administered parenteral drug, such as intravenous (IV) unfractionated heparin. Before beginning treatment with a parenteral anticoagulant, patients who have been taking dabigatran should wait 12 hours if the CrCl is 30 mL/minute or higher or 24 hours after the last dose of dabigatran if the CrCl is below 30 mL/minute.

Surgery. If possible, patients should stop taking dabigatran before invasive or surgical procedures because of an increased risk of bleeding. They should stop taking the drug one to two days before the procedure if the CrCl is 50 mL/minute or greater and three to five days before surgery if the CrCl is below 50 mL/minute.

Commentary: Atrial fibrillation, which affects more than 2 million Americans, involves rapid, uncoordinated contractions of the heart’s two upper heart chambers and is one of the most common types of abnormal heart rhythm. Patients with this arrhythmia are at a higher risk for developing blood clots, which can cause a disabling stroke if a clot travels to the brain.

Dabigatran is an anticoagulant that inhibits thrombin, an enzyme involved in blood clotting. The safety and efficacy of dabigatran were studied in a comparative trial of warfarin. In the trial, patients taking dabigatran had fewer strokes than those who took warfarin. Patients taking warfarin are required to undergo periodic monitoring with blood tests; such monitoring is not necessary with dabigatran.

As with other approved anticlotting drugs, the most common adverse reaction with dabigatran was bleeding, which was sometimes life-threatening and fatal. Gastrointestinal symptoms, including dyspepsia, stomach pain, nausea, heartburn, and bloating, were also reported.


Lurasidone HCl (Latuda)

Manufacturer: Sunovion Pharmaceuticals, Inc., Fort Lee, N.J.

Indication: Lurasidone HCl is an atypical antipsychotic agent indicated for the treatment of patients with schizophrenia.

Drug Class: This psychotropic agent belongs to the chemical class of benzo-isothiazol derivatives. Its chemical name is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione HCl. The empirical formula is C28H36N4O2S • HCl, and the molecular weight is 529.14.

Uniqueness of Drug: The mechanism of action of lurasidone, as with other drugs having efficacy in schizophrenia, is unknown. It is thought that lurasidone’s efficacy in schizophrenia is mediated through a combination of central dopamine type-2 (D2) and serotonin type-2 (5-HT2A) receptor antagonism.

Boxed Warning: Elderly patients with dementia-related psychosis who are given antipsychotic drugs are at an increased risk of death. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared with 2.6% in the placebo group. Lurasidone is not approved for the treatment of dementia-related psychosis.

Warnings and Precautions:

Increased mortality in elderly patients with dementia-related psychosis. Elderly patients with dementia-related psychosis who receive antipsychotic drugs have higher mortality rates. Lurasidone is not approved for patients with dementia-related psychosis.

Cerebrovascular adverse reactions, including stroke. In placebo-controlled trials with risperidone (Risperdal, Janssen), aripiprazole (Abilify, Bristol-Myers Squibb/Otsuka), and olanzapine (Zyprexa, Eli Lilly) in elderly subjects with dementia, there was a higher incidence of cerebrovascular accidents and transient ischemic attacks, including fatalities, compared with placebo-treated subjects. Lurasidone is not approved for patients with dementia-related psychosis.

Neuroleptic malignant syndrome. A potentially fatal symptom complex, sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported in association with antipsychotic drugs, including lurasidone. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

Tardive dyskinesia. Potentially irreversible, involuntary dyskinetic movements can develop in patients who take antipsychotic agents.

Metabolic changes. Atypical antipsychotics have been associated with metabolic changes (e.g., hyperglycemia, dyslipidemia, and weight gain) that may increase cardiovascular or cerebrovascular risk. Prolactin elevations may also occur.

Blood disorders. Leukopenia, neutropenia, and agranulocytosis have been reported with the use of antipsychotic agents.

Orthostatic hypotension and syncope. Dizziness, tachycardia or bradycardia, and syncope may occur, especially early in treatment.

Seizures. Lurasidone should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Potential for cognitive or motor impairment. Patients taking lurasidone should be advised to use caution when operating machinery.

Body temperature. Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised.

Suicide. The possibility of a suicide attempt is inherent in schizophrenia. Patients considered to be at a high risk for suicide should be closely supervised.

Dysphagia. Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, especially those with advanced Alzheimer’s dementia.

Dosage and Administration: The recommended starting dose of lurasidone is 40 mg once daily with food. Initial dose titration is not required. The maximum recommended dose is 80 mg once daily. Caution should be used when lurasidone is taken in combination with other centrally acting drugs and alcohol.

Commentary: Schizophrenia is a chronic, disabling brain disorder that affects approximately 2.4 million American adults, or 1 in 100 people. Symptoms include hallucinations; delusions; lack of emotion and energy; problems with memory and attention; and an impaired ability to plan, organize, and make decisions.

Once-daily lurasidone HCl has been effective and tolerable, adding to the ability of psychiatrists to address the challenging therapeutic needs of patients with schizophrenia. The drug’s efficacy was established in four six-week controlled studies of adults with schizophrenia, but effectiveness for more than six weeks has not been established in controlled studies. Therefore, physician who prescribe lurasidone for extended periods should periodically re-evaluate the drug’s long-term usefulness for each patient.


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