New Drugs of 2006

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Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

1. Discuss the clinical indications of the new drugs approved by the FDA in 2006.

2. Explain the various mechanisms of action of the drugs discussed within this program.

3. Recognize the clinically relevant drug interactions for the drugs reviewed in this program.

4. Identify the most common adverse reactions for the new drugs approved in 2006.

5. Explain the approved dosing guidelines and recommended dosage adjustments for the drugs reviewed.

During 2006, the FDA approved many unique and important medications. Due to space constraints and the large number of new drugs approved during the past year, I have selected 9 for in-depth review in this continuing education program.

The drug reviews include the FDA-approved indication for each drug, current dosing guidelines, contraindications to therapy, and common adverse effects. This article is designed to focus on the new molecular entities and biological approvals that may be unique or with which pharmacists will most likely come into contact. The reader is directed to the Table for a complete list of the new molecular entities and biologicals approved by the FDA during 2006.

Insulin Human Inhalation Powder (Exubera)

Pfizer Laboratories

Exubera is the first inhaled human insulin, and it is indicated for the treatment of adult patients with diabetes mellitus for the control of hyperglycemia. It has an onset of action similar to rapid-acting insulin analogs and a duration of glucose-lowering activity comparable to subcutaneously administered regular human insulin. In patients with type 1 diabetes, inhaled human insulin should be used in regimens that include a longer-acting insulin. In patients with type 2 diabetes, it can be used as monotherapy or in combination with oral agents or longer-acting insulins.

The initial dosage of inhaled human insulin should be individualized and determined based on the physician's advice in accordance with the needs of the patient. Recommended initial premeal doses are based on clinical trials in which patients were requested to eat 3 meals per day. Initial premeal doses may be calculated using the following formula: body weight (kg) ? 0.05 mg/kg = premeal dose (mg), rounded down to the nearest whole milligram number.

Human insulin inhalation powder is a white to off-white powder in a unitdose blister. Each unit-dose blister contains a 1-or 3-mg dose of insulin in a homogeneous powder formulation. A 1- mg blister of inhaled human insulin is approximately equivalent to 3 international units (IU) of subcutaneously injected regular human insulin. A 3-mg blister is approximately equivalent to 8 IU of subcutaneously injected regular human insulin.

After an inhaled human insulin blister is inserted into the inhaler, the patient pumps the handle and then presses a button, causing the blister to be pierced. The insulin inhalation powder is then dispersed into the chamber, allowing the patient to inhale the aerosolized powder.

Under standardized in vitro test conditions, inhaled human insulin delivers a specific emitted dose of insulin from the mouthpiece of the inhaler. A fraction of the total particle mass is emitted as fine particles capable of reaching the deep lung. Up to 45% of the 1- mg blister contents and up to 25% of the 3-mg blister contents may be retained in the blister.

Inhaled human insulin may be used during intercurrent respiratory illness (eg, bronchitis, upper respiratory tract infection, and rhinitis). Close monitoring of blood glucose concentrations and dose adjustment may be required on an individual basis. Inhaled medicinal products (eg, bronchodilators) should be administered prior to administration of inhaled human insulin.

Inhaled human insulin differs from regular human insulin because of its rapid onset of action. When used as mealtime insulin, the dose of inhaled human insulin should be given within 10 minutes before a meal. Hypoglycemia is the most commonly reported adverse event from insulin therapy, including inhaled human insulin. The timing of hypoglycemia may differ among various insulin formulations.

Inhaled human insulin is contraindicated in patients who smoke or who have discontinued smoking less than 6 months prior to starting therapy. If a patient starts or resumes smoking, inhaled human insulin must be discontinued immediately because of the increased risk of hypoglycemia, and an alternative treatment must be utilized. The safety and efficacy of inhaled human insulin in patients who smoke have not been established.

Inhaled human insulin is contraindicated in patients with unstable or poorly controlled lung disease, because of wide variations in lung function that could affect absorption and increase the risk of hypoglycemia or hyperglycemia.

The following nonrespiratory adverse events were reported during inhaled human insulin therapy: hypoglycemia, chest pain, dry mouth, and ear events in pediatric patients, including otitis media and ear pain. The following respiratory adverse events were reported: cough, dyspnea, pharyngitis, increased sputum, and epistaxis.

In clinical trials up to 2 years in duration, patients treated with inhaled human insulin demonstrated a greater decline in pulmonary function, specifically in the forced expiratory volume in 1 second (FEV¹) and the carbon monoxide diffusing capacity, than comparator-treated patients. The mean treatment group difference in pulmonary function, favoring the comparator group, was noted within the first several weeks of treatment with inhaled human insulin, and it did not change over the 2-year treatment period.

Because of the effect of inhaled human insulin on pulmonary function, all patients should have a spirometry (FEV¹) assessment prior to initiating this therapy. Assessment of pulmonary function (eg, by spirometry) is recommended after the first 6 months of therapy and annually thereafter, even in the absence of pulmonary symptoms. In patients who have a decline of =20% in FEV¹ from baseline, pulmonary function tests should be repeated. If the =20% decline from baseline FEV¹ is confirmed, inhaled human insulin should be discontinued.

A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring. The following are examples of substances that may reduce the blood glucose-lowering effect of insulin that may result in hyperglycemia: corticosteroids, danazol, diazoxide, diuretics, sympathomimetic agents (eg, epinephrine, albuterol, and terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (eg, in oral contraceptives), protease inhibitors, and atypical antipsychotic medications (eg, olanzapine and clozapine).

The following are examples of substances that may increase the blood glucose-lowering effect of insulin and susceptibility to hypoglycemia: oral antidiabetic products, angiotensin-converting enzyme inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, propoxyphene, salicylates, and sulfonamide antibiotics. Beta-blockers, clonidine, lithium salts, and alcohol may either increase or reduce the blood glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

Inhaled human insulin is supplied as an Exubera Kit, which contains an Exubera inhaler, a replacement canister, 1-mg ? 180 blisters, 3-mg ? 90 blisters, and 2 Exubera release units. A fully assembled Exubera inhaler consists of the inhaler base, a chamber, and an Exubera release unit. A fully assembled inhaler is packaged with a replacement chamber. The Exubera inhaler can be used for up to 1 year from the date of first use, and the Exubera release unit in the Exubera inhaler should be changed every 2 weeks.

In addition to the Exubera Kit, Exubera is available in combination packs (1-and 3-mg blisters with a release unit) and patient packs (1-or 3-mg blisters with a release unit). Replacement inhalers and components are available.

Lubiprostone (Amitiza)

Sucampo Pharmaceuticals/Takeda Pharmaceuticals/TAP Pharmaceuticals

Lubiprostone is indicated for the treatment of chronic idiopathic constipation in adults. It is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum.

Lubiprostone acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A-independent fashion. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby increasing the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. The recommended dosage is 24 mcg taken twice daily orally with food. Lubiprostone is contraindicated in patients with a history of mechanical gastrointestinal obstruction. Patients with symptoms suggestive of mechanical gastrointestinal obstruction should be evaluated prior to initiating lubiprostone treatment.

Lubiprostone may cause nausea. If nausea occurs, concomitant administration of food with lubiprostone may reduce symptoms.

The drug should not be administered to patients who have severe diarrhea. Patients should be aware of the possible occurrence of diarrhea during treatment. If it becomes severe, the patient should consult a physician. The incidence of diarrhea does not appear to be dose-dependent. No serious adverse events were reported for electrolyte imbalance in the 6 clinical trials, and no clinically significant changes were seen in serum electrolyte levels while patients were receiving lubiprostone.

Lubiprostone is supplied as 24-mcg capsules in bottles containing 100 capsules.

Papillomavirus Quadrivalent Human Vaccine (Types 6, 11, 16, 18) (Gardasil)

Merck & Co Inc

Papillomavirus vaccine is a noninfectious recombinant, quadrivalent vaccine prepared from the highly purified virus-like particles of the major capsid (L1) protein of human papillomavirus (HPV) types 6, 11, 16, and 18. Papillomavirus quadrivalent human vaccine is indicated for girls and women 9 to 26 years of age for the prevention of the following diseases caused by HPV types 6, 11, 16, and 18, for example: cervical cancer, genital warts, and certain precancerous or dysplastic lesions. The papillomavirus vaccine can prevent the following precancerous or dysplastic lesions: cervical adenocarcinoma in situ, cervical intraepithelial neoplasia (CIN) grade 2 and grade 3, vulvar intraepithelial neoplasia grade 2 and grade 3, vaginal intraepithelial neoplasia grade 2 and grade 3, and lowgrade CIN (grade 1).

Gardasil is a prophylactic vaccine. No clear evidence appeared of protection from disease caused by HPV types for which patients were polymerase chain reaction-positive and/or seropositive at baseline. Individuals who were already infected with 1 or more vaccine- related HPV types prior to vaccination were protected from clinical disease caused by the remaining vaccine HPV types.

HPV causes squamous cell cervical cancer and cervical adenocarcinoma, as well as ~35% to 50% of vulvar and vaginal cancers. HPV also causes genital warts (condyloma acuminata), which are growths on the cervicovaginal, vulvar, and external genitalia that rarely progress to cancer. HPV 6, 11, 16, and 18 are common HPV types.

HPV vaccine should be administered intramuscularly as 3 separate 0.5-mL doses according to the following schedule: first dose at elected date, second dose 2 months after the first dose, and third dose 6 months after the first dose. The vaccine should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.

Adverse effects associated with administration of the HPV vaccine are injection-site reactions such as pain, swelling, erythema, and pruritus. Systemic adverse effects experienced 1 to 15 days after vaccine administration are fever, nausea, and dizziness. Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of papillomavirus vaccine should not receive further doses of vaccine.

The vaccine is supplied as cartons of one or ten 0.5-mL single-dose vials or as cartons of one or six 0.5-mL single-dose prefilled Luer-Lok syringes, preassembled with the Ultra Safe Passive Delivery System.

Ranolazine (Ranexa)

CV Therapeutics

Ranolazine is indicated for the treatment of chronic angina; however, it will not abate an acute angina episode. Because ranolazine prolongs the QT interval, it should be reserved for patients who have not achieved an adequate response with other antianginal drugs. Ranolazine should be used in combination with amlodipine, ?-blockers, or nitrates.

The effect on the angina rate or exercise tolerance appeared to be smaller in women than in men. Ranolazine has antianginal and anti-ischemic effects that do not depend on reductions in heart rate or blood pressure. The exact mechanism of action of ranolazine is unknown. It does not increase the rate-pressure product, a measure of myocardial work, at maximal exercise.

Ranolazine dosing should be initiated at 500 mg twice daily and increased to 1000 mg twice daily, as needed, based on clinical symptoms. Ranolazine may be taken with or without meals. The tablets should be swallowed whole and not crushed, broken, or chewed. Dose adjustments of ranolazine generally are not required on the basis of age or gender or in patients with congestive heart failure (CHF) or diabetes mellitus.

Ranolazine is contraindicated in patients with preexisting QT prolongation; in patients with hepatic impairment (Child-Pugh Class A [mild], B [moderate], or C [severe]); in patients receiving QT-prolonging drugs; and in those receiving potent and moderately potent CYP3A inhibitors, including diltiazem. Ranolazine has been shown to prolong the QTc interval in a dose-related manner. Although the clinical significance of the QTc prolongation in the case of ranolazine is unknown, other drugs with this potential have been associated with torsades de pointes-type arrhythmias and sudden death.

With repeat dosing, the mean effect on the QTc of ranolazine 1000 mg twice daily, at T^max, is about 6 msec. In 5% of the population, however, the prolongation of the QTc is 15 msec. Age, weight, gender, race, heart rate, CHF New York Heart Association Class I to IV, and diabetes have no significant effect on the relationship between the ranolazine plasma level and an increase in the QTc. The relationship between ranolazine levels and the QTc remains linear over a concentration range up to 4- fold greater than the concentrations produced by 1000 mg twice daily and is not affected by changes in heart rate. Doses >1000 mg twice daily should not be used.

No studies have examined the effects of ranolazine in patients who have a preexisting QT prolongation or who are receiving other QT-prolonging drugs. Because of possible additive effects on the QT interval, ranolazine should be avoided in patients with known QT prolongation (including congenital long QT syndrome, uncorrected hypokalemia); in patients with a known history of ventricular tachycardia; and in patients receiving drugs that prolong the QTc interval, such as Class Ia (eg, quinidine) and Class III (eg, dofetilide, sotalol) antiarrhythmics and antipsychotics (eg, thioridazine, ziprasidone). Because the QTc-prolonging effect is increased approximately 3-fold in patients with hepatic dysfunction, ranolazine is contraindicated in patients with mild, moderate, or severe liver disease.

Ranolazine should be avoided in patients receiving drugs that are potent or moderately potent inhibitors of CYP3A, including, for example, ketoconazole, HIV protease inhibitors, macrolide antibiotics, diltiazem, and verapamil. Ranolazine is a P-glycoprotein (Pgp) substrate, and caution should be exercised when coadministering ranolazine and Pgp inhibitors such as ritonavir and cyclosporine. Additionally, the dose of simvastatin and digoxin and other Pgp substrates may have to be reduced when ranolazine is coadministered.

Ranolazine may cause dizziness and lightheadedness. Therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.

Ranolazine may cause headache, constipation, nausea, and asthenia, and small, reversible elevations in serum creatinine and blood urea nitrogen levels have been observed in clinical studies with ranolazine. These elevations were observed without evidence of renal toxicity.

Ranolazine increases blood pressure by ~15 mm Hg in patients with severe renal impairment. Blood pressure should be monitored regularly after initiation of ranolazine in such patients. Ranolazine is supplied as 500-mg tablets in bottles containing 60 and 500 tablets.

Rasagiline (Azilect)

Teva Neuroscience Inc

Rasagiline is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. Rasagiline is an irreversible monoamine oxidase (MAO) inhibitor that inhibits MAO type B, but adequate studies to establish whether rasagiline is selective for MAO type B (MAO-B) in humans have not yet been conducted.

The recommended rasagiline dose for the treatment of Parkinson's disease patients is 1 mg administered once daily. If rasagiline is used as adjunctive therapy, the recommended initial dose is 0.5 mg administered once daily. If a sufficient clinical response is not achieved, the adjunctive therapy dose may be increased to 1 mg administered once daily. When rasagiline is used in combination with levodopa, a reduction of the levodopa dosage may be considered based on individual response.

Rasagiline plasma concentrations will increase in patients with hepatic impairment. Patients with mild hepatic impairment should receive 0.5 mg daily of rasagiline. Rasagiline should not be used in patients with moderate or severe hepatic impairment.

CYP1A2 is the major enzyme responsible for the metabolism of rasagiline. Rasagiline plasma concentrations are expected to double in patients taking concomitant ciprofloxacin and other CYP1A2 inhibitors. Therefore, patients taking these concomitant drugs should take 0.5 mg daily of rasagiline.

Rasagiline should not be administered to patients receiving meperidine. Serious reactions have been precipitated with concomitant use of meperidine (eg, Demerol) and MAO inhibitors, including selective MAO-B inhibitors. These reactions have been characterized by coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse, and death. At least 14 days should elapse between discontinuation of rasagiline and initiation of treatment with meperidine.

For similar reasons, rasagiline should not be administered with the analgesic agents tramadol, methadone, and propoxyphene. Rasagiline should not be used with the antitussive agent dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Rasagiline also is contraindicated for use with St. John's wort, mirtazapine, and cyclobenzaprine.

Like other MAO inhibitors, rasagiline is contraindicated for use with sympathomimetic amines, including amphetamines as well as cold products and weight-reducing preparations that contain vasoconstrictors (eg, pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine). Severe hypertensive reactions have followed the administration of sympathomimetics and nonselective MAO inhibitors. At least 1 case of hypertensive crisis has been reported in a patient taking the recommended doses of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine).

Rasagiline should not be administered along with other MAO inhibitors because of the increased risk of nonselective MAO inhibition that may lead to a hypertensive crisis. At least 14 days should elapse between discontinuation of rasagiline and initiation of treatment with MAO inhibitors.

As with other MAO inhibitors, patients taking rasagiline should not undergo elective surgery requiring general anesthesia. Also, they should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. Rasagiline should be discontinued at least 14 days prior to elective surgery. If surgery is necessary sooner, benzodiazepines, mivacurium, rapacuronium, fentanyl, morphine, and codeine may be used cautiously.

Rasagiline treatment at any dose may be associated with a hypertensive crisis if the patient ingests tyraminerich foods, beverages, or dietary supplements or amines (from OTC medications). Hypertensive crisis, which in some cases may be fatal, consists of marked systemic blood pressure elevation and requires immediate treatment/ hospitalization. MAO in the gastrointestinal tract and liver (primarily type A) is thought to provide vital protection from exogenous amines (eg, tyramine) that have the capacity, if absorbed intact, to cause a hypertensive crisis. If significant amounts of certain exogenous amines gain access to the systemic circulation?eg, tyramine from fermented cheese, red wine, herring, or amines contained in OTC cough/cold medications?they can cause release of norepinephrine, which may significantly increase systemic blood pressure. MAO inhibitors that selectively inhibit MAO-B generally are devoid of the potential to cause a hypertensive crisis at defined relatively low doses at which tyramine sensitivity has been characterized.

The selectivity of rasagiline for inhibiting MAO-B (and not MAO-A) in humans has not been sufficiently characterized to permit rasagiline treatment without restriction of dietary tyramine or amines contained in medications. Even for "selective"MAO-B inhibitors, the selectivity for inhibiting MAO-B typically diminishes and is ultimately lost as the dose is increased beyond particular dose levels.

Patients receiving rasagiline should be instructed about the tyramine content of foods and beverages and amine-containing medications that should be avoided. Patients also should be instructed about the signs and symptoms of marked blood pressure elevation that could represent a hypertensive emergency requiring immediate treatment/hospitalization. These signs include severe headache, blurred vision/visual disturbances, difficulty thinking, stupor/coma, seizures, chest pain, unexplained nausea or vomiting, or signs or symptoms of a stroke.

Severe central nervous system toxicity associated with hyperpyrexia and death has been reported with the combination of tricyclic antidepressants and nonselective MAO inhibitors (eg, phenelzine sulfate, tranylcypromine sulfate) or the selective MAO-B inhibitor selegiline. These adverse events have included behavioral and mental status changes, diaphoresis, muscular rigidity, hypertension, syncope, and death. Serious, sometimes fatal, reactions with signs and symptoms including hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuations, and mental status changes progressing to extreme agitation, delirium, and coma have been reported in patients receiving a combination of selective serotonin reuptake inhibitors?including fluoxetine, fluvoxamine, sertraline, and paroxetine?and nonselective MAO inhibitors or the selective MAO-B inhibitor selegiline. Similar reactions have been reported with serotonin-norepinephrine reuptake inhibitors and nonselective MAO inhibitors or the selective MAO-B inhibitor selegiline.

Adverse reactions associated with rasagiline therapy are flu syndrome, arthralgia, depression, falls, hallucinations, and dyspepsia.

Rasagiline is supplied as 0.5-and 1-mg tablets in bottles containing 30 tablets.

Sitagliptin (Januvia)

Merck & Co Inc

Sitagliptin is indicated as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. It also is indicated as combination therapy in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a peroxisome proliferator-activated receptor gamma (PPAR?) agonist (eg, a thiazolidinedione) when the single agent alone, with diet and exercise, does not provide adequate glycemic control. Sitagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, because it would not be effective in these settings.

Sitagliptin is a dipeptyl peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Sitagliptin increases the concentrations of the active intact hormones, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis.

When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic adenosine monophosphate. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.

The recommended dose of sitagliptin is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPAR?agonist (eg, a thiazolidinedione). Sitagliptin can be taken with or without food. Because dosage adjustment is needed, based on renal function, assessment of renal function is recommended prior to initiation of sitagliptin and periodically thereafter. For patients with moderate renal insufficiency (creatinine clearance [CrCl] =30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to =3.0 mg/dL in men and >1.5 to =2.5 mg/dL in women), the dose of sitagliptin is 50 mg once daily. For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with endstage renal disease requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the timing of hemodialysis.

The most common adverse reactions, reported in =5% of patients treated with sitagliptin and more commonly than in patients treated with placebo, are upper respiratory tract infection, nasopharyngitis, and headache.

Sitagliptin is supplied as 25-, 50-, and 100-mg tablets in bottles containing 30 and 90 tablets.

Varenicline (Chantix)

Pfizer Inc

Varenicline is indicated as an aid to smoking-cessation treatment and is a partial agonist selective for a⁴?² nicotinic acetylcholine receptor subtypes. Varenicline binds with high affinity and selectivity at a⁴?² neuronal nicotinic acetylcholine receptors. The efficacy of varenicline in smoking cessation is believed to be the result of its activity at a subtype of the nicotinic receptor, where its binding produces agonist activity while simultaneously preventing nicotine binding to a⁴?² receptors.

Patients should be instructed to set a date to quit smoking and to initiate varenicline treatment 1 week before the quit date. Patients should be advised that varenicline should be taken after eating and with a full glass of water. Varenicline should be initiated following a 1-week titration. Patients should receive 0.5 mg once daily on days 1 through 3; 0.5 mg twice daily on days 4 through 7; and then the recommended dose of 1 mg twice daily.

Patients should be treated with varenicline for 12 weeks. For those who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks'treatment is recommended to further increase the likelihood of long-term abstinence. Patients who do not succeed in stopping smoking during 12 weeks of initial therapy, or who relapse after treatment, should be encouraged to make another attempt, once factors contributing to the failed attempt have been identified and addressed.

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