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Cytotoxic Agents
Questions
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Q19.1 Concerning cytotoxic drug use in dermatology, what are (1) five to six of the disease categories for which these drugs are used, and (2) the three most important adverse effect categories? (Pg. 209)
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Q19.2 What are (1) the two major categories of cytotoxic agents, (2) major drug examples of each category, and (3) the mechanism for each category concerning the cell cycle? (Pgs. 210, 211, 214)
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Q19.3 Given the major risks of cytotoxic agents, what are the most important patient education issues to discuss before prescribing cytotoxic drugs? (Pg. 211x2 )
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Q19.4 Compared to azathioprine therapy, (1) what is the role of a baseline thiopurine methyltransferase in patients to receive thioguanine, and (2) how does the role of xanthine oxidase differ for these drugs? (Pgs. 211, 212)
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Q19.5 Even though thioguanine (‘6-thioguanine metabolites’) are generally considered the active form of the prodrug azathioprine, what is the process and the immunologic result of the ‘prodrug’ thioguanine conversion to ‘active’ nucleotides? (Pg. 212)
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Q19.6 What is the mechanism of hydroxyurea concerning (1) the enzyme inhibited, and (2) the resultant impact on deoxyribonucleic acid (DNA)? (Pg. 213)
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Q19.7 What are two to three of the unique cutaneous adverse effects of hydroxyurea? (Pg. 214)
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Q19.8 Concerning the prodrug cyclophosphamide, what are (1) the initial inactive metabolites, (2) the active metabolites (good and bad), and (3) its subsequent inactive metabolites? (Pg. 215)
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Q19.9 What are (1) the effects of cyclophosphamide on DNA, and (2) the resultant immunologic effects of this cytotoxic drug? (Pg. 215)
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Q19.10 For which subsets of systemic vasculitis has cyclophosphamide historically provided major therapeutic advances (and still plays a major role)? (Pg. 215)
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Q19.11 Concerning cyclophosphamide and bladder cancer, what is (1) the metabolite responsible, (2) the condition commonly preceding the cancer, (3) the nonmedical preventative measure, and (4) the most effective medical management preventative step? (Pgs. 215x2, 218x2 )
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Q19.12 Concerning malignancy risk from cyclophosphamide or chlorambucil (other than bladder cancer from cyclophosphamide), (1) what malignancies are increased (include one that is ‘unique’), and (2) what populations tend to be at especially increased risk? (Pgs. 217, 220)
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Q19.13 Compare and contrast the mechanism for cyclophosphamide and chlorambucil? (Pg. 219)
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Q19.14 What neurologic adverse effects have been reported with chlorambucil, but not with cyclophosphamide (Pg. 220)
Abbreviations used in this chapter
AE
Adverse effect(s)
CBC
Complete blood count
CML
Chronic myelogenous leukemia
CYP
Cytochrome P-450
FDA
US Food and Drug Administration
PASI
Psoriasis area and severity index
PUVA
Psoralen and ultraviolet A
SAE
Serious adverse effect(s)
TPMT
Thiopurine methyltransferase
WBC
White blood count
Introduction
In dermatology, cytotoxic agents are used to treat severe and/or refractory skin disease. Whereas the therapeutic potential of these agents is great, associated toxicities are substantial. Any therapeutic advantage afforded by these medications must be balanced against the consequences or risks of use.
Q19.1 Skin diseases that may be treated with cytotoxic agents, including recalcitrant psoriasis, mycosis fungoides, connective tissue disease, vasculitis, immunobullous disorders, and neutrophilic dermatoses, to name a few. When treating severe skin disease, cytotoxic agents are typically used at immunomodulatory doses. Certainly, the clinician must remain mindful of the potential for: (1) carcinogenesis, (2) teratogenesis, and (3) myelosuppression, with the increased potential for infection with these agents. Familiarity with dosing regimens, common toxicities, and proper laboratory monitoring, both before and during therapy, is critical to maximize safe use of these drugs ( Table 19.1 ).
Table 19.1
Cytotoxic Agents
| Generic Name | Trade Name | Generic Available | Manufacturer | Formulations (mg) | Special Formulations | Standard Dose Range | Cost (US$) |
|---|---|---|---|---|---|---|---|
| Thioguanine | Tabloid | No | GlaxoSmithKline | 40 mg scored tablet | 40–120 mg/day or 160 mg up to 3× weekly | ∼$10.00 per 40 mg tablet | |
| Hydroxyurea | Droxia, Hydrea | Yes (500 mg capsules only) | Bristol-Myers Squibb | 200 mg tablet, 300 mg tablet, 400 mg tablet; 500 mg capsule | 1.0-1.5 g/day (uncommonly 2 g/day) | ∼$1.00 per capsule | |
| Cyclophosphamide | Cytoxan | Yes | Bristol-Myers Squibb | 25 mg tablet, 50 mg tablet | IV formulation from 500–2000 mg | 1–3 mg/kg/day (PO) | ∼$3.00 per tablet |
| Chlorambucil | Leukeran | No | GlaxoSmithKline | 2 mg tablets | 0.05–0.2 mg/kg/day (initial); 4–10 mg/day (maintenance) | equivalent to cyclophosphamide | |
| Melphalan | Alkeran | No | Celgene | 2 mg | IV formulation 50 mg/10 mL | 1–6 mg/day (initial); 0.05–0.10 mg/kg/day (maintenance) | equivalent to cyclophosphamide and chlorambucil |
IV , Intravenous; PO , by mouth (per os).
Major Subcategories of Cytotoxic Agents and the Cell Cycle
Cytotoxic agents modulate the behavior of cells through inhibition of growth and development. Knowledge of the ‘cell cycle’ ( Fig. 19.1 ) is requisite to understanding the mechanism of action for many of these drugs.
In brief, the cell cycle begins with the G 1 phase, which is directed towards preparing the cellular apparatus for deoxyribonucleic acid (DNA) synthesis. The subsequent S phase is devoted to DNA synthesis. At the end of S phase, G 2 phase, or interphase, occurs, followed by the M phase of actual cell division. Indeed, some cells of the body may enter a G 0 (resting) phase of indeterminate length, awaiting a stimulus or conditions upon which to re-enter the cell cycle.
Q19.2 Cytotoxic drugs may be divided into two general classes, antimetabolites and alkylating agents. Antimetabolites mimic the natural building blocks of the cell and are most active during the S phase, when DNA is being synthesized (‘cell cycle specific’). Antimetabolites commonly used in dermatology include methotrexate (see Chapter 14 ), azathioprine (see Chapter 15 ), mycophenolate mofetil (see Chapter 16 ), topical 5-fluoruracil (5-FU, see Chapter 47 ) along with thioguanine and hydroxyurea (both discussed in this chapter). Conversely, alkylating agents exert their effect through physicochemical interactions with DNA, such as alkylation, cross-linking, and carbamylation, and these effects are independent of the cell cycle (‘cell cycle independent’). Alkylating agents commonly used in dermatology include cyclophosphamide and chlorambucil, with melphalan, used much less commonly (all three drugs discussed in this chapter).
Patient Education Issues
Cytotoxic agents are dangerous medications, used to treat major and possibly even life-threatening skin disease. In this regard, patient education remains an important aspect of appropriate medical care. Q19.3 The substantial risks of these drugs must be balanced against the consequences of a disease undertreated or untreated. Nearly all of these medications are immunosuppressive in nature, and many may also be myelosuppressive.
Q19.3 Potentially lethal infections may arise quickly in an immunosuppressed patient. As such, all patients placed on cytotoxic agents should be queried at each visit for symptoms of infection, such as fever, chills, sweating, shortness of breath, cough, headache, dysuria, and arthritis. Prompt reporting of suspicious symptoms should be encouraged. Myelosuppression, including the risk of excessive bleeding because of thrombocytopenia, is another concern. General instruction about bleeding risks should be provided to patients using these medications. Vigilance with regard to patient education and patient monitoring is critical when using cytotoxic agents.
Antimetabolites
Q19.2 Methotrexate is the quintessential example of an antimetabolite, and its use is so common in dermatology that an entire chapter of this book is devoted to the subject (see Chapter 14 ). Azathioprine is another antimetabolite with a number of important uses in dermatology, and its use is discussed in full elsewhere (see Chapter 15 ). Mycophenolate mofetil is discussed in a separate chapter because of the growing importance of this drug in dermatology (see Chapter 16 ). In addition, 5-FU, which is used chiefly in topical form, is ubiquitous in dermatology (see Chapter 47 ). These medications aside, the remaining antimetabolites of significant importance to dermatology are thioguanine and hydroxyurea ( Fig. 19.2 ).
Thioguanine
Thioguanine (see Fig. 19.2 ) is an antimetabolite from the thiopurine family, and it has a mechanism of action and biometabolism similar to azathioprine (see Chapter 15 ).
Pharmacology ( Table 19.2 )
Thioguanine is administered orally, but it has an incomplete and unpredictable absorption pattern. Upon absorption, the drug is converted by the liver to 6-thioguanilyic acid. This substance is further enzymatically converted to the di- and triphosphates. The half-life of thioguanine is reportedly about 80 minutes (range 25–240 minutes), with peak plasma concentrations about 2 to 4 hours after ingestion. Q19.4 Importantly, thioguanine is not metabolized by xanthine oxidase, and so thiopurine methyltransferase (TPMT) is even more substantially involved in detoxification.
Table 19.2
Key Pharmacological Concepts
| Drug Name | ABSORBTION AND BIOAVAILABILITY | ELIMINATION | ||||
|---|---|---|---|---|---|---|
| Peak Levels (h) | Bioavailable (%) | Protein Binding (%) | Half-Life (h) | Metabolism | Excretion | |
| Thioguanine | 2–4 | 30 (14–46) | 20–30 | 1–2 | Hepatic | Renal |
| Hydroxyurea | 1–2 | ∼100 | (minimal) | 4–5.5 | Unclear | Renal (80%) |
| Cyclophosphamide | 1–2 | ∼75 | 13 | 5–9 | Hepatic | Mostly hepatic |
| Chlorambucil | 1 | 87 (decreased by food) | ∼99 | 1.5 | Hepatic | Hepatic |
| Melphalan | 1 | 58–85 (highly variable) | 60–90 | 1.5 | Hepatic and chemical hydrolysis | Low renal excretion |
Mechanism of Action
Q19.5 Thioguanine is a prodrug that yields nucleoside analogues, which further produce cytotoxic effects, via incorporation into cellular DNA. The resultant apoptosis affects chiefly activated T lymphocytes, and the clinical benefit is related to actual decreased T-lymphocyte counts in skin lesions.
Clinical Use
Off-Label Dermatologic Uses
In dermatology, thioguanine is used chiefly as a third-line agent for the treatment of psoriasis. Thioguanine has been used rarely to treat lupus and atopic dermatitis ( Box 19.1 ).
Box 19.1
Thioguanine—Indications and Contraindications
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US Food and Drug Administration-Approved Indications
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Remission induction and consolidation in acute nonlymphocytic leukemia
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Off-Label Dermatologic Uses
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Psoriasis
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Dermatitis
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Severe atopic dermatitis (very rarely)
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Connective tissue disease
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Lupus erythematosus (for cutaneously-limited disease, also very rarely)
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Contraindications
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Absolute
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Drug allergy
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Relative
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History of hepatovenular occlusive disease (see text)
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Hematologic disorders
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Infection (active)
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Pregnancy Prescribing status—Category D
Psoriasis
Zackheim and associates reported on the 18-year experience of one institution using thioguanine for the treatment of psoriasis, and the medication was effective, but with a narrow therapeutic window. In a more recent retrospective study of patients with recalcitrant psoriasis, 14 of 18 patients experienced more than 90% improvement with thioguanine, including patients with psoriatic arthritis, palmoplantar disease, or scalp involvement.
Contraindications
Drug allergy is an absolute contraindication to thioguanine. Thioguanine is in pregnancy category D. Use of low-dose thioguanine in pregnant women has been reported for inflammatory bowel disease, but in dermatology, use in pregnancy is avoided.
Adverse Effects
The most common adverse effects (AE) of thioguanine are myelosuppression and gastrointestinal disturbances.
Myelosuppression
In the largest series of patients using thioguanine for psoriasis, just under half experienced myelosuppression, yet only 20% required discontinuance. Thrombocytopenia was the earliest indicator of myelosuppression in one series. Pulsed dosing of thioguanine has been associated with a lower rate of myelosuppression, but TPMT testing was not performed in this study.
Gastrointestinal Effects
Gastrointestinal disturbances occurring with thioguanine use include nausea, excessive flatulence, taste changes, esophageal reflux, and diarrhea, but these AE are usually tolerated without discontinuance. In a single study, elevated liver transaminases occurred in 25% of patients, yet many had been on methotrexate before thioguanine use. In general, thioguanine is not considered particularly hepatotoxic, particularly in comparison to alternative agents used for similar purposes (e.g., methotrexate). Liver biopsy is not indicated during thioguanine treatment, but rare cases of toxic hepatic venoocclusive disease have been reported. AE are summarized in Box 19.2 .
Box 19.2
Thioguanine—Adverse Effects
Gastrointestinal
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Gastrointestinal distress (often tolerated without discontinuance)
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Includes nausea, excessive flatulence, taste changes, esophageal reflux, and diarrhea
Hematologic
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Myelosuppression (single most common AE, may begin as thrombocytopenia)
Hepatic
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Toxic hepatitis (less common than with other cytotoxic agents)
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Hepatovenular occlusive disease (rare, see text)
Metabolic
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Hyperuricemia
Infectious
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Potential increased incidence of opportunistic infection with myelosuppression
AE , Adverse effect(s).
Drug Interactions
The metabolism of thioguanine is independent of xanthine oxidase, and it may be administered concurrently with allopurinol or febuxostat without dose reduction. Aminosalicylates may inhibit TPMT activity, and it may be prudent to minimize or avoid concurrent use of such medications.
Monitoring Guidelines
All patients contemplating use of thioguanine should undergo a thorough history and physical examination. Patients with hematologic disturbances or active infection should be excluded from use. Women of childbearing age should clearly receive pregnancy tests. Q19.4 Recommended baseline laboratory studies include complete blood count (CBC), with manual differential and platelet count, liver function studies, and a TPMT assay, with the latter used to guide the starting dose.
With continued use of thioguanine, repeat blood counts and liver function studies should be performed, weekly at first, transitioning to biweekly as the dose stabilizes, then monthly for 3 months, and quarterly thereafter. Repeat laboratory tests should be performed with any dose escalation. Safety guidelines to employ during use of thioguanine are summarized in Box 19.3 .
Box 19.3
Safety Monitoring for Thioguanine Use
Initial Evaluation
Baseline Laboratories
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Ongoing Laboratory Monitoring
Follow-Up Clinical Evaluation
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BUN , Blood urea nitrogen; CBC , complete blood count.
Therapeutic Guidelines
Thioguanine is supplied as 40-mg tablets. Although it was tradition to begin with a 40 mg/day dose, in the latest review of thioguanine use in severe psoriasis, where TPMT levels were assessed before treatment, patients with high levels of TPMT expression were dosed successfully with 80 mg/day from the start. A pulsed regimen of 100 to 120 mg twice weekly, increasing up to 160 mg 3 times weekly, has also been reported to be effective.
Hydroxyurea
Hydroxyurea (see Fig. 19.2 ) was first synthesized by Dressler and Stein in 1869.
Pharmacology
Hydroxyurea is well-absorbed, with peak serum levels occurring within 1 to 2 hours of dosing; tissue effects are noted within 5 hours, peak at 8 hours, and persist for up to 20 hours.
The metabolism of hydroxyurea is incompletely understood. One important metabolite appears to be acetohydroxamic acid. Ultimately, up to 80% of the drug is excreted by the kidneys. Another degradation pathway may be urease found in intestinal bacteria. The drug has short plasma half-life of 4 to 5.5 hours, with negligible amounts of hydroxyurea in the body 24 hours after dosing (see Table 19.2 ).
Mechanism of Action
Q19.6 Hydroxyurea impairs DNA synthesis through inhibition of ribonucleotide diphosphate reductase, an enzyme that reduces nucleotides to deoxynucleotides. This limits the supply of DNA bases available for synthesis, resulting in strand breakage and cell death. Hydroxyurea is also a radiation sensitizer. Lastly, through hypomethylation, hydroxyurea alters gene expression, and it is thought this effect may lead to improved differentiation in psoriatic skin. Hydroxyurea is most effective in cells with a high proliferative index, as it acts upon cells entering the S phase of the cell cycle, and it is preferentially concentrated within leukocytes.
Clinical Use
In dermatology, hydroxyurea has been used ‘off label’ in the treatment of acute febrile neutrophilic dermatosis (Sweet syndrome), erythromelalgia, and hypereosinophilic syndrome, but the drug is used principally as a third-line agent for treatment of psoriasis ( Box 19.4 ).
Box 19.4
Hydroxyurea—Indications and Contraindications
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US Food and Drug Administration-Approved Indications
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For management of some forms of melanoma (metastatic and gastrointestinal), treatment-resistant chronic lymphocytic leukemia, some ovarian carcinomas, and concomitantly, with radiation therapy, in local management of squamous cell carcinoma of the head and neck (except for that of the lip).
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Off-Label Dermatologic Uses
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Erythromelalgia
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Hypereosinophilic syndrome
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Psoriasis (most important and well-documented use in dermatology)
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Sweet syndrome
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Contraindications
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Absolute
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Drug allergy
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Relative
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Cardiopulmonary disease (particularly that exacerbated by anemia)
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Hematologic disorders (including chronic anemia)
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Hepatic disease
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Infection (active)
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Renal disease
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Pregnancy Prescribing Status—Category D
Psoriasis
Hydroxyurea treatment has been reported chiefly for classic plaque-type disease, but it may play a role in management of guttate and erythrodermic psoriasis. Its role in pustular psoriasis is more controversial. Suggestion that patients refractory to methotrexate or psoralen and ultraviolet A (PUVA) are also refractory to treatment with hydroxyurea, has been refuted.
No large double-blinded clinical trials of hydroxyurea use in psoriasis exist, but small studies suggest a beneficial effect. In an early series of 60 patients treated with hydroxyurea for severe psoriasis, 50% to 60% achieved a response, while in another more recent series of 85 patients treated with hydroxyurea, for a mean duration of 16 months, about 60% of patients achieved complete to near complete clearing of psoriasis, using dosages of 0.5 to 1.5 g/day. In another nonrandomized series of 31 patients with recalcitrant psoriasis, 75% of patients treated with 1 to 1.5 g/day of hydroxyurea showed at least a 35% reduction in the Psoriasis Area and Severity Index (PASI) score and 55% had a greater than 70% reduction in the PASI score. A recent comparison study of methotrexate (15–20 mg weekly) versus hydroxyurea (3–4.5 g weekly) was undertaken in 30 patients and revealed a 77% reduction in mean PASI score among methotrexate users, versus a 49% reduction in mean PASI score among hydroxyurea users.
When hydroxyurea is effective, a response generally first occurs within 2 to 4 weeks, with maximal improvement at 6 to 8 weeks. Because hydroxyurea has little hepatic toxicity, it is considered by some as an alternative for psoriasis treatment in those with contraindications to use of methotrexate. However, other experts instead reserve hydroxyurea use for combination regimens or as maintenance therapy once clearance has been achieved via other means.
Contraindications
A known allergic reaction to hydroxyurea is an absolute contraindication to its use. Because of myelosuppression, the drug is relatively contraindicated in patients with known leukopenia (white blood count [WBC] <3500/mm 3 ), thrombocytopenia (<100,000/mm 3 ), or severe anemia. Hydroxyurea is pregnancy category D, and its use in pregnant women is generally avoided, particularly in dermatology, where many therapeutic alternatives exist.
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