Pharmacy Times

Bringing Hope Home with Oral Antineoplastic Agents

Author: Monica Holmberg, PharmD & Guido R. Zanni, PhD

Behavioral Objectives

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

  1. Describe the risks and benefits of oncology's historical reliance on intravenous (IV) administration of antineoplastic chemotherapy.
  2. List reasons why oral chemotherapy is often a desirable or necessary intervention.
  3. Elucidate the challenges researchers face when developing oral chemotherapy.
  4. Describe how oral and IV forms of certain antineoplastic agents differ in side effects and administration.
  5. Address how the increase in oral chemotherapy availability has affected the Medicare program, hospice programs, and patients.
  6. Discuss barriers that prevent effective use of oral chemotherapy.
  7. Implement interventions designed to improve treatment adherence and ultimate outcomes for patients.

Adiagnosis of cancer is often the most difficult for a physician to communicate and very difficult for a patient to receive. Most patients describe it as profoundly upsetting, despite the fact that the prognosis for certain cancers is considerably better than ever before, and the probability of partial or complete remission is often high. Patients, stunned by the very word cancer, often envision painful death. This reaction is nothing new. In the 1940s, Franklin Delano Roosevelt's Works Progress Administration made posters to heighten people's awareness of cancer and the importance of early intervention. At the time, however, only 3 options were available, and they did not include drugs (Figure 1).

Although certain cancers remain difficult to treat and often do lead to rapid death, treatment for many cancers has led to longer survival and complete remission for many patients. Surviving cancer is becoming increasingly more common, and some cancers have become more like chronic diseases in that patients will die with the cancer, rather than from the cancer. Table 11-3 describes the most common cancers; the 5-year survival rates (the point at which oncologists consider the patient cured) for patients of all ages; and incidences of occurrence in older Americans. These incidences are important because seniors have a cancer rate almost 10 times that of people younger than 65 years of age, and they are 16 times more likely to die of cancer.1 In addition, treating seniors with oral chemotherapy (the focus of this article) necessitates special concerns.

In the United States, most chemotherapy has been administered intravenously, and oral chemotherapy has been supplemental to intravenous (IV) therapy, or in exceptional cases a stand-alone treatment. Many clinicians considered oral chemotherapy to involve "pale imitations"of IV drugs.4 Lately, however, more agents (with agents being defined as drugs and biologics) are available in oral dosage forms, and more than one quarter of the 400 antineoplastic agents now in the pipeline are planned as oral agents.5 Why is there such interest in oral chemotherapy?

Whereas the basic cost of IV agents usually is less than that of their oral equivalents, administering IV medication generally is more costly than administering oral medication. Placement of a central line, supplies, nursing time, pumps,6,7 and hospital admission (when necessary) can rapidly inflate costs.8 In addition, patients generally prefer oral treatment7; they like its convenience and flexibiltiy,9 and they also perceive that they are more in control. In cases where chronic administration may be necessary?ie, when agents are cytostatic (such as the tyrosine kinase inhibitors, all of which end in the suffix -inib), given to address or prevent metastases, or used for chemoprevention?IV administration becomes undesirable and very costly or inconvenient.

IV administration of medication is associated with a higher rate of complication, including infection.6 Some IV formulations require solvents that present potential problems during the infusion (eg, Cremophor EL for paclitaxel, which has been associated with hypersensitivity reactions and affects the pharmacokinetic properties of paclitaxel, especially in patients with hepatic dysfunction10). Using an oral formulation would eliminate the solvent problem.11

Oral agents are sometimes as effective as their parenteral counterparts, but they can possess improved side-effect profiles4,9 and may be better tolerated. Topotecan, for example, is equally efficacious in oral or IV form, but the toxicity profile of the oral form is better.12 Also, if an agent must be given at a specific time during the treatment cycle, oral dosage forms can ensure exposure at that exact time if the patient is fully adherent.11

 

Oral formulations are not recommended for everyone?ie, not for patients who have had upper gastrointestinal (GI) surgery; patients with head or neck cancers that impede swallowing or cause dysphagia; or patients who are too young to handle capsules or tablets.4 For most patients, however, oral formulations can be an excellent choice. Table 2 lists currently available oral antineoplastic agents.

Stick or Swallow

Manufacturers'goals when formulating an oral dosage form would be improved efficacy with an equal or better side-effect profile and improved patient convenience (eg, 1 small tablet per dose rather than 9 large capsules per dose).13 Manufacturers also would target reduced interpatient and intrapatient variability.14

IV dosage forms are fairly simple in comparison. If the agent is physically stable in a diluent and passes safety and sterility testing, it can be administered by the IV route, and it will circulate throughout the patient's system immediately. The dose given is the available dose, bypassing tissue-absorption barriers.13 Adherence is assured as soon as the infusion is complete.

Such is not the case with oral dosage forms. The ideal oral dosage form must be structurally stable at gastric pH, have a reproducible dissolution profile, and be able to cross the intestinal epithelial membrane (called acceptable hydrophilic/lipophilic balance).9,11 Saturable bioavailability (decreased bioavailability as the dose increases, such as that demonstrated by etoposide and leucovorin) is a problem.4,7 Oral formulations must be free of significant GI toxicities, because inducing nausea, vomiting, or diarrhea would affect absorption and adherence. The formulations also should be palatable for patients.15

GI Barriers

Fortunately and unfortunately, the GI tract uses 2 mechanisms in addition to normal flora, secretory immunoglobulins, and pH to erect barriers to the absorption of an agent or invader: P-glycoprotein (P-gp) and cytochrome P-450 enzymes. This situation is fortunate because these mechanisms protect individuals from xenobiotics, or substances foreign to the body, such as pesticides, insecticides, environmental compounds, and other chemicals. This situation is unfortunate when the xenobiotic happens to be an antineoplastic agent that could be beneficial to the patient.11

The energy-requiring P-gp efflux pump is a 170-kD, large cell-surface protein occurring normally in the colon, small intestine, adrenal glands, kidney, and liver. (It is also expressed by tumor cells and is a modulator of multidrug resistance; it mediates transport of antineoplastic agents out of tumor cells.11,13,14) If the cell were a nightclub, P-gp would be its bouncer, throwing rowdy patrons or aggressive interlopers out the door. Table 2 lists agents that encounter difficulty with P-gp. Wide distribution of P-gp not only impedes drug uptake from the gut into the bloodstream, but also from the bloodstream into organs such as the brain and the testes. Likewise, its positioning facilitates active excretion by the kidney and the liver (via the biliary system).11

Cytochrome P-450 is a heme-based electron-carrying enzyme that inserts one of the oxygen atoms of the molecule O2 into its substrates. Because oxidative reactions are a primary contributor to drug metabolism, this mixed-function oxidative system is of concern for many antineoplastic agents.7,16 Its important roles occur in the liver and the adrenal cortex.11,13 If this environment were a nightclub, cytochrome P-450 would be a Mickey Finn-wielding bartender, incapacitating unwelcome patrons so that they could be carried off.

Concentrations of the most important cytochrome P-450 isoenzyme in terms of drug metabolism (CYP3A4) vary significantly between individuals, with a potential 10-fold difference.14,17 Figure 2 describes the drug-absorption process from ingestion to excretion. In cancer patients with advanced disease, liver function and increased alpha-1 glycoprotein levels are good predictors of CYP3A4 activity. This enzyme may account for up to 18% of interpatient variability. Elevated inflammatory markers (particularly C-reactive protein) may account for an additional 44% of interpatient variability, because it also affects CYP3A4.17 Table 2 notes those agents that are CYP4A3 substrates.

As pharmacists well know, the presence or absence of food also can affect drug absorption. Often, food decreases absorption. Frequently, when food improves absorption, bile salt may be the substance that enables dissolution.8 Grapefruit juice is a notorious CYP enzyme inducer, as are cruciferous vegetables (eg, broccoli, cabbage), charred/grilled meats, red wine and alcohol, and cigarette smoke.7 Administration of concomitant drugs or complementary/alternative medicines also may complicate oral drug absorption.18

Currently, only a few noninvasive methods exist that can predict a patient's P-gp or CYP3A4 status. Some researchers and drug manufacturers have used the erythromycin breath test to measure CYP3A4 levels, in which radioactive erythromycin is administered. The patient exhales into a balloon- type device every 5 minutes for 30 minutes, and the flux of 14CO2 is measured as a percentage of the dose. Midazolam also has been used. This technology is not widely available and is still controversial.18

If P-gp or cytochrome P-450 issues seem to be a problem for an agent's oral absorption, 2 approaches seem logical. Researchers can try to alter a drug's affinity for P-gp expressed in intestinal epithelium, or they can try to alter the formulation in some way to increase extraction in the gut.11 Doing so may increase availability and, in the case of expensive agents, lower cost. In some cases, researchers have tried coadministering a P-gp inhibitor such as cyclosporin A, verapamil, quinidine, or amiodarone to increase drug availability. These efforts have met with mixed results.8,13,14 Clearly, some of these agents also are costly.

The Barriers

Formulating and testing oral agents can be time-consuming and costly. Addressing safety, establishing the maximum tolerable dose of different formulations, identifying new metabolites, and examining food or drug interactions are all necessary.11 Recent advances have successfully identified agents that can differentiate between cancerous and normal cells. They exploit differences, but their specific actions must be examined carefully (taking more time), because they can have unexpected effects.4 Additionally, our understanding of the science of prodrugs (compounds that undergo chemical conversion by metabolic processes to become active pharmacologic agents; drug precursors) has grown substantially in the past decade.15 Capecitabine demonstrates both concepts. It targets tumor cells that overexpress thymidine phosphorylase and is a prodrug of 5-fluorouracil.

Traditionally, most antineoplastic doses have been calculated using body surface area (BSA) or weight in an effort to negate interpatient variability.4 The theory that BSA could be used to calculate dosing originated in 1958, when researchers noted that it correlates closely with cardiac output. It was believed that cardiac output correlates with blood flow to the liver and the kidneys and in this way influences agent elimination.19 In 1966, a French researcher found that, by scaling doses to body weight raised to the 2/3 power, maximum tolerable doses were approximately equivalent among species.20,21 Because BSA is only approximately equivalent to body weight raised to the 2/3 power, but easier to calculate, clinicians substituted BSA. Several formulas, with the most popular being the Dubois and Dubois, are used to calculate BSA.22

A school of thought now exists that questions whether BSA dosing is necessary or appropriate. The Dubois and Dubois formula was originally proposed in 1916.23 It was based on tests conducted in only 9 people, some of whom were not representative of a mainstream population.22,23 Permutations of the formula have been made throughout the generations for convenience. Cardiac output and renal and hepatic perfusion are not as important to drug elimination as once thought.22 Genetic and environmental factors play a strong role. No BSA formula takes into account weight that is disproportionate to height.24 To deal with obese patients, clinicians sometimes cap BSA at 2.2 m2 (ie, all patients whose BSA exceeds 2.2 m2 would be treated with doses calculated using 2.2 m2). Others use ideal weight, but both methods lack any firm scientific backing.25

BSA dosing sometimes presents a further problem when oral formulations are used, and the argument for flat dosing (like that used for most nonantineoplastic drugs) is strong. Otherwise, dose rounding is necessary, and the combination of multiple tablets in different strengths can be confusing to the patient.4 Flat dosing is easier for patients, and it allows the manufacturer to formulate fewer strengths of the oral dosage form.

Despite the developmental costs and issues surrounding oral chemotherapy, more than 20 oral chemotherapeutics are currently FDA-approved and are used in a wide range of cancers.4 Some agents are older and are available as inexpensive generics, and new agents are becoming available quickly. A few agents that are approved for diseases other than cancer are now employed as off-label antineoplastics to treat cancers alone or in combination with other treatment. For example, thalidomide is approved only for erythema nodosum leprosum, but it is also used to treat prostate cancer in combination with docetaxel and for multiple myeloma.26

Adherence: Does Diagnosis Matter?

Adherence is a problem with most oral medication. For the lay population, adherence refers to the act or process of sticking with something. By using the terms adherence and nonadherence, however, we can avoid the impression that clinicians judge patients when they fail to follow directions, introduce an element of equality in the clinician-patient relationship, and reinforce the fact that patients may choose not to follow health professionals' advice. In medicine, adherence is the extent to which patients' behaviors are consistent with the medical advice they have been given.

A patient's adherence to a medication regimen is largely determined by his or her assessment of risks and benefits.9 Other factors are important too, such as the economics of filling or refilling a prescription (see sidebar); the number of dosage units per dose or per day; dosing frequency; and side effects. In general, patients tend to be fairly adherent when they start a drug regimen (approximately 20% of new prescriptions and 85% of refills are never filled27) and over time become less so. Long-term adherence across classes of drugs and diseases is believed to be less than 50%.9 Over the years, most clinicians have presumed that cancer patients, because of the gravity of their disease, would be model adherers.9 Unfortunately, this presumption is incorrect.28-31

Adherence occurs in a continuum, from total nonadherence (treatment dropout) to adherence above and beyond what has been recommended (ie, if 1 is good, 2 is better). Table 3 describes the repercussions of nonadherence in different types of antineoplastic chemotherapy. Patients may or may not tell their clinicians that they are nonadherent, and clinicians sometimes do not have the communication skills they need to detect nonadherence or to promote adherence. These communication breakdowns may lead prescribers to increase doses, assuming that the cancer is progressing despite treatment or that the previously prescribed dose is too low. A lack of appreciation of the necessity to adhere to the regimen may cause patients to perceive that the health care provided is inadequate, when indeed their adherence is the real issue.9

Pediatric and Senior Patients

Children present special adherence problems. One might expect excellent adherence, because a young child's parents are responsible for administering medication, and failure to do so could result in disease progression or death. Yet, approximately one third of children and adolescents are seriously or occasionally nonadherent.27,32 Sometimes, their parents do not understand the treatment protocol. Children may find oral medication difficult to swallow or unpalatable; parents may find forcing a gravely ill child to take medication too emotionally draining and thus forgo doses. Adherence also is inversely related to the number of siblings a child has; perhaps caring for more than 1 child impacts the parents' ability to adhere to the regimen.32

Adolescents who have cancer create a particular challenge. Their nonadherence increases precipitously at about 20 weeks after diagnosis.9,32 The belief that they are indestructible or peer pressure may play a role.

Pharmacists can expect to dispense more oral chemotherapy to elders in the future. As previously noted, more than half of all cancers occur in people 65 years of age or older. Seniors often tolerate chemotherapy as well as younger patients do.7 Oncologists should create treatment plans that are as aggressive as the tumor warrants and that the elder can tolerate, using observation, history, laboratory work, and radiologic studies.

Currently, the likelihood of receiving full-dose chemotherapy (and other treatments) decreases with age.33,34 Clinicians sometimes decrease seniors' doses, thinking that these patients will be less tolerant of the antineoplastic agents than younger people. Researchers believe, however, that, absent specific contraindications, standard fulldose chemotherapy without dose reduction is not only reasonable but essential in the elderly. Treatment modifications should be based on measurable physiologic changes only. Research has shown that elders benefit from chemotherapy in a way similar to younger patients, and effective ways to deal with treatment-related toxicities exist.33 Oncology and geriatrics share a mantra: Treat the individual patient.

For seniors, medication concerns related to antineoplastics include all of those familiar to pharmacists for other drug therapies: comorbid disease, polypharmacy, variable nutritional status, underlying health, renal or hepatic decline, changes in body fat/lean tissue/ total body water ratio, and other physiologic changes. In the GI tract, decreased acid secretion, slower emptying time, less mobility, and decreased splanchnic blood flow can alter absorption of oral drugs. Additionally, seniors accumulate membrane P-gp, which leads to multidrug resistance to available antineoplastics more quickly than in younger patients.7 Moreover, the fact that people older than age 70 have half as many pluripotent blood progenitor cells can contribute to increased myelotoxicity. 7 Fortunately, supportive therapies for patients who experience chemotherapy-induced myelotoxicity have advanced considerably, and side effects including myelosuppression are not the issue they once were.

The Logistics

Pharmacists who have not dispensed many oral antineoplastics and pharmacies that have not traditionally carried many antineoplastics often have concerns about potential health risks from exposure to these agents while preparing or administering them. They look for reasonable protective measures to use while counting out uncoated oral doses and tablets from multidose bottles, unit-dosing uncoated tablets in a unit-dose machine, crushing tablets to make oral liquid doses, or compounding powders into custom-dosage capsules. Studies have confirmed some health effects such as skin rashes, adverse reproductive outcomes, and possibly leukemia and other cancers after workplace exposures to hazardous drugs. Risk is directly related to the extent of exposure and the potency and toxicity of the hazardous drug.

Reasonable steps to follow when oral antineoplastic chemotherapy is introduced to the pharmacy are as follows:

For more information, read the National Institute for Occupational Safety and Health's publication 2004-165: Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings, available at www.cdc.gov/niosh/docs/2004-165.

The Pharmacist's Role

Pharmacists, because of their frequent contact with cancer patients who take oral chemotherapy, play a pivotal role in improving adherence and ensuring that medications are taken correctly. One concern about the use of oral chemotherapy is that it decreases contact frequency with the oncology team.4 The clear solution is to invite the pharmacist to be an active member of the team, providing support to the patient and communicating adherence concerns to clinicians.

Adherence can be improved in several ways. Education provided by all members of the team serves to reinforce the adherence message and leads to improved outcomes. Behavioral modification techniques, reminders and cues, and various devices designed to improve adherence (eg, daily medication boxes, beeping caps) all help.9 Pharmacists can take or encourage other steps as well:

Summary/Conclusion

The increased availability of oral antineoplastic chemotherapy heralds a new age in cancer treatment. New mechanisms of action promise better results when these agents are used alone or with other agents that have complementary mechanisms. Patient convenience also is a clear advantage. Some barriers still exist, however, including physiologic hurdles and adherence concerns.

Pharmacists should prepare themselves to see a larger assortment of oral medications for cancer, and more patients with prescriptions in hand and questions ready. A practiced familiarity with the issues unique to oral chemotherapy will help patients bring the hope of total remission and long life home in the form of a prescription vial.

Acknowledgment

The authors wish to thank Jeannette Yeznach Wick, RPh, MBA, senior clinical research pharmacist, National Cancer Institute in Bethesda, Md, for her guidance and review. Opinions expressed herein are the authors'and not necessarily those of any government agency.

Monica Holmberg, PharmD: Pharmacist, Phoenix Children's Hospital, Phoenix, Ariz; Guido R. Zanni, PhD: Psychologist, Health Systems Consultant, Alexandria, Va

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@mwc.com.

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(Based on the article starting on page 103.) Choose the 1 most correct answer.

1. Which of the following sentences is false?

  1. Surviving cancer is becoming increasingly less common, and some cancers become chronic diseases.
  2. Five-year survival is the point when oncologists considered the patient cured.
  3. Seniors have a cancer rate almost 10 times that of people less than age 65 and are 16 times more likely to die of cancer.
  4. Some cancers become chronic diseases for patients, who often die of other causes than cancer.

2. Traditionally:

  1. No drugs have been available to treat cancer; radiation or surgery has been used.
  2. Intravenous (IV) drugs have been preferred for their convenience and lack of complications.
  3. IV drugs have been used to treat almost all cancers.
  4. Oral drugs have been used only as supportive care to treat drug-induced side effects.

3. Which of the following is false?

  1. IV drugs are often less costly than their oral counterparts.
  2. The cost of oral antineoplastic agents is less than that of IV antineoplastic agents because the development process is much less complicated.
  3. When developing IV and oral antineoplastics, manufacturers must look at safety, stability, and sterility.
  4. The cost of oral antineoplastic agents is more than that of IV antineoplastic agents, because the development process is much more complicated.

4. Patients prefer oral therapy to IV therapy because:

  1. It is more convenient.
  2. It is more flexible.
  3. They feel that they have more control.
  4. All of the above

5. Reasons why oral antineoplastics are attractive to oncologists include all of the following except:

  1. Oral therapies have fewer serious complications.
  2. Oral therapies sometimes circumvent solvent problems.
  3. Oral therapies are always more effective than their IV counterparts.
  4. Oral therapies that are cytostatic can be given chronically.

6. Cytostatic tyrosine kinase inhibitors:

  1. End in the suffix -zumab.
  2. Are in the development process and close to FDA approval.
  3. Include imatinib.
  4. Should be given once monthly for 3 months.

7. Oral antineoplastic chemotherapy is ideal for patients who:

  1. Are ambulatory and have a cancer that will need chronic treatment.
  2. Have had upper gastrointestinal (GI) surgery.
  3. Have head or neck cancers that impede swallowing.
  4. Have dysphagia or are too young to handle capsules or tablets.

8. Which of the following does not influence oral formulations?

  1. Gastric pH
  2. Cytochrome P (CYP)-450 enzymes
  3. Location of the cancer
  4. P-glycoprotein (P-gp)

9. The ideal oral formulation would have all of the following properties except:

  1. No significant GI toxicities.
  2. Palatable taste.
  3. Improved agent efficacy with an equal or better side-effect profile.
  4. Dosing based on body surface area calculations.

10. P-gp is not:

  1. A 170-kilodalton, large cell-surface protein.
  2. A cytokine occurring normally in the colon, small intestine, adrenal glands, kidney, and liver.
  3. A modulator of multidrug resistance.
  4. A mediator of antineoplastic agent transport out of tumor cells.

11. CYP-450 is not:

  1. A heme-based electron-carrying enzyme that inserts one of the oxygen atoms of the molecule O2 into its substrates.
  2. A promulgator of mixed-function oxidative reactions.
  3. A small concern in relation to antineoplastic agents.
  4. A substance with important roles in the liver and the adrenal cortex.

12. Which of the following sets of foods includes CYP enzyme inducers?

  1. Grapefruit, cruciferous vegetables, charred/grilled meats, red wine and alcohol, and cigarette smoke
  2. Grapefruit, cruciferous vegetables, pressure-cooked meats, red wine and alcohol, and cigarette smoke
  3. Grapefruit, cruciferous vegetables, charred/grilled meats, grape-based beverages, and cigarette smoke
  4. Citrus fruit, cruciferous vegetables, charred/grilled meats, red wine and alcohol, and cigarette smoke

13. The erythromycin breath test is:

  1. A test to determine adherence to antibiotic therapy for myelosuppression- related infection.
  2. Available at almost all cancer centers in the United States.
  3. Somewhat invasive in that the patient must prepare for several days before it is administered.
  4. A noninvasive test to determine CYP3A4 status in individual patients.

14. Using body surface area for chemotherapy dosing:

  1. Is a relatively new concept developed in the 1990s.
  2. Is based on findings from a study by Crick and Watson in 1916.
  3. Was originally designed so that interspecies dose equivalents could be determined easily.
  4. Is the ideal way to calculate oral doses.

15. Thalidomide is FDA-approved only for:

  1. Erythema nodosum leprosum.
  2. Prostate cancer in combination with docetaxel.
  3. Multiple myeloma.
  4. a and c

16. A common assumption that has been proven untrue is:

  1. Cancer patients are less adherent with oral medications than other patients because they often have chemotherapy-induced GI effects.
  2. Cancer patients will always be more adherent with oral medications because of the gravity of their disease.
  3. Adherence to IV medications is not an issue; patients never miss clinic visits.
  4. Cancer patients need less prompting and education to be adherent.

17. Among pediatric patients, which group has the greatest adherence issues?

  1. Newborns
  2. Toddlers
  3. Preteens
  4. Adolescents

18. Elderly patients who have been diagnosed with cancer:

  1. Should receive reduced doses of antineoplastic chemotherapy because they cannot tolerate the side effects.
  2. Should be treated prophylactically for all possible side effects because the likelihood is high that they will experience all of them.
  3. Benefit from chemotherapy as younger patients do, and from effective ways to deal with treatment- related toxicities that exist.
  4. Are notoriously nonadherent to therapy.

19. Some reasonable steps to take when oral antineoplastic chemotherapy is introduced to the pharmacy include:

  1. Read all information and material safety data sheets prepared by the manufacturer for each oral antineoplastic.
  2. Have all staff fitted for respiratory protection devices.
  3. Gown up, put on gloves, and use a respirator while counting.
  4. Count the capsules or tablets in the palm of the hand, so that traces of antineoplastic agents do not contaminate the counting tray.

20. Pharmacists should be prepared to:

  1. Counsel patients about what to do if they vomit while taking an oral antineoplastic agent.
  2. Spend extra time with adolescents and parents of young children to go over their therapy carefully.
  3. Answer questions such as "How long will [discomfort/nausea/side effects] last?"or "Will [hair loss/skin discoloration/side effects] be permanent?"
  4. All of the above