Mexican Pharmacy Blog

The FDA has approved incobotulinumtoxinA (Xeomin, Merz) to treat blepharospasm and cervical dystonia. This neurotoxin inhibits the release of acetylcholine, thereby reducing muscle contractions. A boxed warning mentions the risk of distant spread of the toxin’s effect, which can cause symptoms of botulism such as asthenia, muscle weakness, blurred and double vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and life-threatening swallowing and breathing problems. Caution is advised when Xeomin is used with aminoglycoside antibiotics or other agents that interfere with neuromuscular trans – mission, such as curare-like compounds. Xeomin is discussed in this month’s Pharmaceutical Approval Update column on page 526.

Epoetin alfa Help In Healing Hip Fractures

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Intertrochanteric hip fracture is a threat to older people for a number of reasons, including the danger of blood loss, especially if the patient is anemic. If autologous blood isn’t available, allo – genic blood transfusion comes with its own risks for older anemic patients. Researchers from Levadia, Greece have proposed an alternative: epoetin alfa (e.g., Procrit, Ortho-Biotech; Epogen, Amgen). The authors divided 79 patients with hip fracture into two groups; one group received 10 daily doses of epoetin alfa 20,000 IU beginning from the day of trauma, and the other group received placebo. There was a statistically significant difference between the two groups in the required units of allogenic blood used. Patients receiving epoetin alfa also had higher hematocrit and hemoglobin values, with a statistically significant difference at seven days after surgery, compared with the control group. The mean follow-up period was 34 months. Three patients were lost to follow-up, although they were doing well at their last examination. Eight patients died of causes not directly related to the hip fracture or to epoetin alfa. Complications were considered minor. Five patients had a skin inflammatory response or bruising; one patient had chills and fever after the fifth injection. None of the patients had to stop therapy because of adverse effects. Patients also received 100 mg of parenteral iron each day. Six patients reacted to the iron, but all responded favorably to a reduced infusion. Epoetin alfa was also cost-effective, according to the researchers. The total cost of therapy was roughly 85% of the cost of preparing and conserving 1 unit of allogenic blood.

Acetaminophen Raises Risk of Asthma and Eczema in Teens

Recent reports have linked acetaminophen use to asthma in children. Studies are now linking acetaminophen to asthma and eczema in adolescents. Teenagers who used the drug monthly had more than double the risk of asthma compared with teens who did not use it. Yearly use was linked to a 50% increase in asthma risks. As part of the International Study of Asthma and Allergies in Childhood (ISAAC), questionnaires were given to more than 300,000 13- and 14-year-olds in 113 centers in 50 countries. “Medium” users, who took acetaminophen once in the preceding year, had a 43% higher asthma risk and a 31% higher eczema risk compared with non-users. “High” users, who had used the drug within the previous month, had 2.51 times the risk of asthma and a 99% greater risk of eczema compared with non-users. The risk of rhino conjunctivitis was also 38% higher for medium users and 2.39 times greater for high users than for non-users. A causal relationship was suggested. It is thought that acetaminophen has a systemic inflammatory effect, which could increase oxygen stress owing to depletion of glutathione-dependent enzymes, resulting in enhanced Th2 allergic immune responses. It is also possible that the drug suppresses the immune response to rhino virus infections, a common cause of severe asthma in children. Some investigators believe that acetaminophen use is a factor in the increased incidence of asthma worldwide. In earlier studies, acetaminophen reduced levels of glutathione, an antioxidant found in the lungs. Another study mentions an increased incidence of asthma and wheezing in people taking acetaminophen.

The FDA has warned that lamotrigine (Lamictal, GlaxoSmithKline), which isindicated for treating seizures and bi – polar disorder, can cause aseptic meningitis. The agency is working with the company to update the prescribing information and the patient medication guide. A rare but serious side effect of lamotrigine use, aseptic meningitis can also be caused by viruses, toxic agents, some vaccines, and autoimmune disease. Symptoms may include headache, fever, chills, nausea, vomiting, stiff neck, and sensitivity to light. When meningitis is suspected, lamo – trigine should be discontinued if no other cause of meningitis is identified.

The drug was approved in December 2004. Since then and continuing through November 2009, 40 cases of aseptic meningitis have been identified in patients taking the product. Of these 40 patients, 35 needed hospitalization. Symptoms generally resolved after the drug was discontinued. In 15 cases, even more severe symptoms returned when patients resumed taking the drug.

Source: FDA, August 12, 2010

SSRIs Lack Benefit for Autism

Antidepressants commonly prescribed to people with autistic spectrum disorders should not be recommended at this time, according to a new study. Despite some evidence of benefits in adults with autism, there appears to be no evidence for any benefits associated with selective serotonin reuptake inhibitors (SSRIs) in children, who may experience serious adverse drug effects. Although SSRIs are widely prescribed, they have not been specifically approved for use in autism. In the U.K., most antidepressants are not approved for children for any condition. The rationale behind the use of SSRIs in autism is that they act on serotonin, which affects some of the psychological processes affected by the condition.

Cochrane researchers included seven trials of 271 patients in their study. They evaluated fluoxetine (Prozac, Eli Lilly), fluvoxamine (Luvox, Solvay), (Celexa, Forest), and fenfluramine (removed from the U.S. market). Overall, the investigators found no benefit in the five trials in children and did find some evidence of serious harm, including one child who had a prolonged seizure after taking citalopram. In the two trials for adults, symptoms improved, but there was too little evidence for the drugs to be recommended. A problem with analyzing the results was that each trial used different measures for assessing the drugs’ effects. The researchers said that decisions about using SSRIs for coexisting obsessive-compulsive disorder, aggression, anxiety, or depression in patients with au tism could be made on a case-by-case basis.

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Antidepressant drugs are medicines that relieve symptoms of mental depression.
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Antidepressant drugs are used to treat serious, continuing mental depression that interferes with a person’s ability to function. Everyone feels sad, “blue,” or discouraged occasionally, but usually those feelings do not interfere with everyday life and do not need treatment. However, when the feelings become overwhelming and last for weeks or months, professional treatment can help. Although depression is one of the most common and serious mental disorders, it is also one of the most treatable. According to the American Psychiatric Association, 80-90% of people with depression can be helped. If untreated, depression can lead to social withdrawal, physical complaints, such as fatigue, sleep problems, and aches and pains, and even suicide.

The first step in treating depression is an accurate diagnosis by a physician or mental health professional. The physician or mental health professional will ask questions about the person’s medical and psychiatric history and will try to rule out other causes, such as thyroid problems or side effects of medicines the person is taking. Lab tests may be ordered to help rule out medical problems. Once a person has been diagnosed with depression, treatment will be tailored to the person’s specific problem. The treatment may consist of drugs alone, counseling alone, or drugs in combination with counseling methods such as psychotherapy or cognitive behavioral therapy.

Antidepressant drugs help reduce the extreme sadness, hopelessness, and lack of interest in life that are typical in people with depression. These drugs also may be used to treat other conditions, such as obsessive compulsive disorder, premenstrual syndrome, chronic pain, and eating disorders.

Antidepressant drugs, also called antidepressants, are thought to work by influencing communication between cells in the brain. The drugs affect chemicals called neurotransmitters, which carry signals from one nerve cell to another. These neurotransmitters are involved in the control of mood and in other responses and functions, such as eating, sleep, pain, and thinking.

The main types of antidepressant drugs in use today are:

• Tricyclic antidepressants, such as amitriptyline (Elavil 75 mg), imipramine (Tofranil), nortriptyline (Pamelor)
• Selective serotonin reuptake inhibitors (SSRIs or serotonin boosters), such as fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft)
• Monoamine oxidase inhibitors (MAO inhibitors), such as phenelzine (Nardil), and tranylcypromine (Parnate)
• Lithium (used mainly to treat manic depression, but also sometimes prescribed for recurring bouts of depression).

Selective serotonin reuptake inhibitors act only on the neurotransmitter serotonin, while tricyclic antidepressants and MAO inhibitors act on both serotonin and another neurotransmitter, norepinephrine, and may also interact with other chemicals throughout the body. Selective serotonin reuptake inhibitors have fewer side effects than tricyclic antidepressants and MAO inhibitors, perhaps because selective serotonin reuptake inhibitors act only on one body chemical, serotonin.

Because the neurotransmitters involved in the control of moods are also involved in other processes, such as sleep, eating, and pain, drugs that affect these neurotransmitters can be used for more than just treating depression. Headache, eating disorders, bed-wetting, and other problems are now being treated with antidepressants.

All antidepressant drugs are effective, but certain types work best for certain kinds of depression. For example, people who are depressed and agitated do best when they take an antidepressant drug that also calms them down. People who are depressed and withdrawn may benefit more from an antidepressant drug that has a stimulating effect.

Recommended dosage depends on the kind of antidepressant drug, the type and severity of the condition for which it is prescribed, and other factors such as the patient’s age. Check with the physician who prescribed the drug or the pharmacist who filled the prescription for the correct dosage.
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While antidepressant drugs help people feel better, they cannot solve problems in people’s lives. Some mental health professionals worry that people who could benefit from psychotherapy rely instead on antidepressant drugs for a “quick fix.” Others point out that the drugs work gradually and do not produce instant happiness. The best approach is often a combination of counseling and medicine, but the correct treatment for a specific patient depends on many factors. The decision of how to treat depression or other conditions that may respond to antidepressant drugs should be made carefully and will be different for different people.

Always take antidepressant drugs exactly as directed. Never take larger or more frequent doses, and do not take the drug for longer than directed.

Most antidepressant drugs do not begin working right away. The effects may not be felt for several weeks. Continuing to take the medicine is important, even if it does not seem to be working at first.

Side effects depend on the type of antidepressant drug.

Antidepressant drugs may interact with a variety of other medicines. When this happens, the effects of one or both of the drugs may change or the risk of side effects may be greater. Some interactions may be life-threatening. Anyone who takes antidepressant drugs should let the physician know all other medicines he or she is taking.

Periodicals

• Johnson, Lois. “Daylight for Depression.” Total Health, 16 (December 1994): 14.
• Sacra, Cheryl. “The New Cure-alls: Mood Lifters May Offer Handfuls Of Hope for More Than Just Depression.” Health, 22 (September 1990): 36.
• “Treatment of Depression: Drugs Alone Are Not Enough.” HealthFacts, 20 (February 1995): 189.

Milnacipran has been used for several years in Europe and Asia for treating patients with depression. It was approved in 2009 as Savella in the U.S. for patients with FM. As with older drugs used for FM, milnacipran utilizes both norepinephrine and serotonin reuptake as its primary mechanisms for treating symptoms. Pregabalin and duloxetine are also used for FM. Besides FDA-approved agents, several medications have off-label usage in therapy for FM, such as gaba-pentin (Neurontin, Pfizer), tramadol (Ultram Mexico, PriCara), and amitriptyline.

In January 2010, the efficacy and safety of milnacipran were called into question. Public Citizen, a non-profit consumer advocacy group, petitioned the FDA to remove the drug from the market because of its hypertensive effects and lack of long-term evidence.20 The average increase in systolic and diastolic BP was 3.1 mm Hg with milnacipran; almost 20% of non-hypertensive patients receiving milnacipran 100 mg/day became hypertensive at the end of the study. The average increase in BP seen with milnacipran is comparable to that of other SNRIs on the market. Compared with venlafaxine and duloxetine, milnacipran has the highest selectivity for norepinephrine reuptake.

Although scrutiny should be used in prescribing milna cipran, it is still a valid option for FM based on the clinical evidence. Additional long-term studies of milnacipran are still needed because it is being used to treat a chronic disease state. One must consider the patient’s current medication profile, financial means, and coexisting disease states in order to select the most appropriate treatment.

The efficacy and tolerability of milnacipran were evaluated in a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose trial of adults with FM. Patients received milnacipran 100 mg/day or 200 mg/day or placebo for 15 weeks.

Patients were eligible for enrollment if they:

• were between 18 and 70 years of age.
• had a diagnosis of primary FM, based on 1990 ACR criteria.
• had withdrawn from centrally active therapies commonly used to treat FM.
• had discontinued treatment using transcutaneous electrical nerve stimulation (TENS), biofeedback, acupuncture, anesthetic or narcotic patches, or injections for tender and trigger points.
• had a raw score of 4 or higher on the physical function component of the Fibromyalgia Impact Questionnaire (FIQ) and 40 or more out of 100 on the mean VAS pain score.

Patients were excluded from the study if they:

• had severe psychiatric illness.
• displayed current major depressive illness based on the Mini-International Neuropsychiatric Interview or had a score higher than 25 on the Beck Depression Inventory.
• exhibited a significant suicide risk.
• were abusing alcohol, benzodiazepines, or other drugs.
• had a history of behavior that prohibited compliance.
• had coexisting cardiovascular, pulmonary, hepatic, renal, GI, or auto-immune disease (except for Hashimoto’s or Graves’ disease that has been stable for three months before screening).
• had a systemic infection at the time.
• currently had cancer (except for basal cell carcinoma), unstable endocrine disease, severe sleep apnea, prostate enlargement or other genitourinary disorder.
• were pregnant or breast-feeding.

The study took place at 86 centers in the U.S. from November 2004 to December 2006. Before the trial, therapies that had the potential to interfere with pain symptoms of FM had to be discontinued. Of the 2,270 patients who were screened, 1,196 received milnacipran 100 mg/day, milnacipran 200 mg/day, or placebo, given as two daily doses.

Patients entered a one-week to four-week period for washout of prohibited medications, followed by a two-week baseline assessment period. Milnacipran-treated patients received 12.5 mg on day 1, 12.5 mg twice daily for two days, 25 mg twice daily for four days, and 50 mg twice daily for seven days. Patients receiving 200 mg/day received 100 mg twice daily for seven days; all other patients underwent a sham dose escalation to maintain blinding. After the escalation, the dosage was unchanged from week 3 to 15 (a total of 12 weeks). Any patient who was intolerant of the medication was dropped from the trial.

Baseline demographics in all treatment arms were similar. The primary efficacy measure was a composite response rate based on these endpoints:

• pain improvement of 30% or more in VAS 24-hour morning recall
• Patient Global Impression of Change (PGIC) ratings of “very much improved” or “much improved”
• an improvement of 6 points or more on the Medical Outcome Short-Form 36 (SF-36) Physical Component Summary (PCS) score

After 15 weeks, a significantly greater number of patients receiving milnacipran 100 mg/day and 200 mg/day achieved the primary endpoints of meeting the three criteria for a FM composite response versus placebo (milnacipran doses of 100 mg/day, P = 0.01; milnacipran doses of 200 mg/day, P = 0.02). The number of patients experiencing more than a 30% improvement from baseline with 24-hour pain was highest with milnacipran 200 mg/day (39.9%), compared with 100 mg/day (37.3%) or placebo (28.7%).

The most frequently reported AE with the study drug was nausea, which occurred in 37.6% of patients taking 200 mg/day, in 34.3% of those taking 100 mg/day, and in 19.2% taking placebo. Other commonly reported AEs were dizziness, palpitations, hot flushes, hypertension, vomiting, tachycardia, hyperhidrosis, constipation, and migraines. Discontinuation rates attributable to AEs were higher with milnacipran than with placebo (23.7% with 200 mg/day, 19.5% with 100 mg/day, and 9.5% with placebo). Overall, milnacipran showed significant efficacy over placebo for treating FM; however, the higher dose of 200 mg/day was associated with more AEs.

A total of 100 mg/day is given in divided doses. The recommended dose-titration schedule for milnacipran is:

• Day 1: 12.5 mg once daily
• Days 2–3: 25 mg/day (12.5 mg twice daily)
• Days 4–7: 50 mg/day (25 mg twice daily)
• After day 7: 100 mg/day (50 mg twice daily)

The manufacturer recommends an initial dose of 12.5 mg/day given once daily on day 1. On days 2 and 3, the dose should be increased to 25 mg/day, taken as 12.5 mg twice daily. On days 4 to 7, the dose should be further increased to 50 mg/day, taken in divided doses of 25 mg twice daily. After day 7, the dose should reach 100 mg/day, taken as 50 mg twice daily. The dose may be increased to reach 200 mg/day, given as 100 mg twice daily; however, doses should not exceed 200 mg/day because of the lack of evidence for the drug’s efficacy and because of an increased risk of AEs.
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Dose adjustments should be made for each patient. As commonly seen with other SNRIs, tapering of the dose is needed when the drug is discontinued. Patients should not stop milnacipran therapy abruptly because of the potential for the development of withdrawal symptoms.

Renal Insufficiency

No dose adjustments are needed for patients with mild renal impairment (a creatinine clearance [CrCl] of 50–80 mL/minute); caution should be applied in patients with moderate renal impairment (CrCl, 30–49 mL/minute). For patients with severe renal insufficiency (CrCl, 5–29 mL/minute), the maintenance dose should be reduced by 50% to 50 mg/day in divided doses of 25 mg twice daily. Milnacipran should not be prescribed for patients with end-stage renal disease.

Hepatic Insufficiency

No dosage adjustments are necessary for patients with hepatic impairment; however, caution should be taken in this patient population.

Elderly Patients

In the phase 3 studies of the safety and efficacy of milnacipran for treating FM, no overall differences were observed in patients 60 years of age or older in comparison with younger patients. Specific trials involving milnacipran for geriatric patients with FM have not been published, although safety has been analyzed in older patients with depression. In a study comparing milnacipran with imipramine (Tofranil, Malinckrodt), milnacipran was associated with lower withdrawal rates and fewer AEs (except for nausea) in patients 65 years of age and older. Although there were fewer AEs in the milnacipran group, dry mouth was the only statistically more frequent AE seen with imipramine.

Pregnant and Lactating Women

Milnacipran has been designated as a Pregnancy Category C agent, implying positive fetal risks in animal studies, but studies involving humans are lacking. The manufacturer states that no adequate or well-controlled studies have been reported for pregnant women. Milnacipran should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.
Controlled studies of milnacipran have not been performed in nursing mothers. Milnacipran is excreted in animals, and simultaneous nursing is therefore not recommended.

Pediatric Populations
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No controlled studies involving milnacipran for FM have included patients younger than 17 years of age. Consequently, the drug’s safety and efficacy have not been established in this patient population.

The chemical name of milnacipran HCl is (±)-[1R(S),2S(R)]-2-(amino-methyl)-N,N-diethyl-1-phenylcyclopane-carboxamide HCl. Its empirical formula is C15H23ClN2O; the molecular weight is 282.8 g/mol. Milnacipran is a white to off-white crystalline powder with a melting point of 179° C. It is freely soluble in water, methanol, ethanol, chloroform, and methylene chloride and is sparingly soluble in diethyl ether.

Milnacipran savella is sold as orally administered, film-coated tablets in dosages of 12.5, 25, 50, and 100 mg of the active ingredient. It is also supplied in a dose-titration pack for patients starting treatment. According to the manufacturer, the tablets should be stored between 59°F and 86°F.

Milnacipran is a SNRI that inhibits the reuptake of both norepinephrine and serotonin; it also has a mild affinity for inhibiting N-methyl-D-aspartate (NMDA).5 Milnacipran exerts higher selectivity for norepinephrine reuptake than venlafaxine (Effexor generic price, Wyeth) or duloxetine.

The exact mechanism of milnacipran and its efficacy in FM are unknown, but it is hypothesized that the effects on regulating dysfunctional noradrenergic and serotonergic pathways contribute to its therapeutic properties. The selectivity for norepinephrine over serotonin has yet to show an overall clinical advantage, since both neurotransmitters have effects on pain modulation.

Milnacipran does not affect the reuptake of dopamine, and it has no significant affinity for serotonergic (5-HT1–7), dopaminergic (D1–5), opiate, benzodiazepine, and gamma-aminobutyric acid (GABA) receptors in vitro.

Because milnacipran lacks affinity for adrenergic, cholinergic, and histaminergic receptors, it does not exhibit many of the expected adverse effects (AEs) seen with the tricyclic antidepressants (TCAs). It has no significant affinity for Ca2+, K+, Na+, or Cl− channels, and it does not inhibit the activity of the monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase.

Absorption and Distribution
The pharmacokinetic properties of milnacipran are summarized in Table 1. Following oral administration, the drug is rapidly absorbed, exhibiting maximal concentrations at two to four hours and a mean peak concentration (Cmax) of 150 ng/mL after a single 50-mg dose. As a result of its favorable absorption profile, milnacipran exhibits high bioavailability of approximately 85% to 90%. First-pass elimination is limited, especially since there is low variability among subjects tested.10,11 Administration following a meal has no effect on peak plasma levels.

Table 1: Pharmacokinetics of Milnacipran

Milnacipran exhibits low, nonsaturable, plasma protein binding (13%), which is lower than the other approved SNRIs (venlafaxine and duloxetine). Because of its low protein binding, milnacipran is free to diffuse, and it is widely distributed in the body (5.3 ± 0.4 L/kg).