The Egyptian Pharmacovigilance Center (EPVC) Newsletter, April 2026 edition, presents critical safety information for healthcare professionals, including a major regulatory update on isotretinoin prescribing requirements, a detailed local case safety report documenting posterior reversible encephalopathy syndrome (PRES) in two pediatric oncology patients receiving cyclophosphamide-containing chemotherapy.
Safety Notification – Isotretinoin Updated Prescribing Controls and Rising Risks from Misuse
1.1 Background and Therapeutic Context
Isotretinoin (13-cis-retinoic acid) is an oral retinoid derived from vitamin A and remains one of the most effective treatments for severe, nodular, or confluent acne that is unresponsive to conventional therapies, including oral antibiotics and topical treatments. The drug is indicated primarily for cases where there is a risk of permanent scarring.
The regulatory authorities in France (ANSM) and the United Kingdom (MHRA) have recently highlighted a dual focus: optimising safe access to isotretinoin treatment while addressing emerging public health risks linked to misuse. This section synthesises the key updates from both agencies.
1.2 Evolving UK Prescribing Framework (MHRA, effective 22 January 2026)
Following a comprehensive safety review by the Commission on Human Medicines (CHM), the MHRA has updated isotretinoin prescribing requirements. The review found that safety measures introduced in 2023 are working well, with healthcare professionals now spending more time discussing benefits and risks and monitoring patients more closely for side effects.
1.2.1 Key Change: Removal of Second Prescriber Requirement for Under-18s
| Previous Requirement | Updated Requirement (effective 22 January 2026) |
|---|---|
| Treatment for patients under 18 required agreement from a second prescriber | Second prescriber requirement removed; replaced by enhanced risk minimisation measures |
The review found that the two-prescriber requirement was causing potential delays in access to treatment for some under-18s, with minimal evidence of disagreement between prescribers about treatment decisions. The CHM therefore recommended that healthcare professionals can prescribe isotretinoin to under-18s without seeking the agreement of a second prescriber, ensuring young people with severe acne benefit from both safer and more timely access to treatment.
Patients can still request a second opinion from another prescriber if they wish to be reassured that isotretinoin is the best treatment for them.
1.2.2 Strengthened Risk Minimisation Measures
The removal of the second prescriber requirement is supported by a series of enhanced risk minimisation measures:
Healthcare professionals are expected to fully engage in the clinical audit, which will be initiated in 2026.
1.2.3 Core Safety Requirements Remain Unchanged
Despite the streamlining, all core safety requirements remain in effect:
1.3 Growing Concern: Misuse Driven by Social Media (ANSM Alert, March 2026)
The French National Agency for Medicines and Health Products Safety (ANSM) issued a safety alert in March 2026 regarding the misuse of isotretinoin for aesthetic purposes, driven by misinformation circulating on social media platforms.
1.3.1 The “Accutane Nose” Myth
The ANSM has warned against a persistent rumour on social media claiming that isotretinoin can “slim the nose” or “make the nose thinner”. These claims are not evidence-based and fall entirely outside the authorised indications for isotretinoin.
1.3.2 Nature and Extent of the Problem
The ANSM reports that isotretinoin-containing medicines are currently being promoted on social media platforms (particularly TikTok) for aesthetic purposes, including claims of achieving a “finer nose” and “smoother skin”, outside of their authorised therapeutic indications.
The agency emphasises that isotretinoin should never be used for aesthetic purposes under any circumstances.
1.4 Risks of Unsupervised Misuse
Such misuse is particularly concerning given isotretinoin’s well-documented and potentially severe risk profile. The following adverse effects may occur even at low doses and can persist after treatment cessation:
| System | Adverse Effects |
|---|---|
| Teratogenicity (Pregnancy) | Major fetal malformations (including central nervous system, cardiovascular, and craniofacial defects); pregnancy loss |
| Psychiatric | Depression, anxiety, psychotic symptoms, suicidal ideation, and suicide attempts (very rare but reported) |
| Hepatobiliary | Hepatotoxicity, elevated liver enzymes |
| Metabolic | Hyperlipidaemia (elevated triglycerides and cholesterol) |
| Ocular | Dry eye syndrome, corneal opacities, decreased night vision |
| Musculoskeletal | Myalgia, arthralgia, hyperostosis |
| Dermatological | Severe skin dryness, cheilitis, photosensitivity, hair thinning |
| Gastrointestinal | Inflammatory bowel disease (rare but serious) |
Additionally, obtaining isotretinoin without a prescription—particularly via online sources—is illegal and bypasses essential medical safeguards, including pregnancy testing, mental health assessment, and laboratory monitoring.
1.5 Clinical Implications for Healthcare Professionals
1.6 Key Safety Messages
- Isotretinoin access may be streamlined (removal of second prescriber requirement), but safe use depends on strict adherence to prescribing controls
- Use outside approved indications—particularly for cosmetic purposes—is inappropriate, ineffective, and potentially dangerous
- All core safety requirements, including the Pregnancy Prevention Programme, remain fully in effect
- Social media claims about isotretinoin for aesthetic enhancement (e.g., “nose slimming”) are false and dangerous
1.7 International Regulatory Context
Local Case Safety Report – Posterior Reversible Encephalopathy Syndrome in Two Pediatric Oncology Patients Receiving Cyclophosphamide-Containing Chemotherapy
2.1 Case Summary
The Egyptian Pharmacovigilance Center (EPVC) received two serious case reports concerning pediatric oncology patients who developed neurological manifestations following chemotherapy administration. Upon follow-up, both patients were confirmed to have Posterior Reversible Encephalopathy Syndrome (PRES) .
| Parameter | Case 1 | Case 2 |
|---|---|---|
| Age/Sex | 4-year-old male | 4.5-year-old female |
| Primary cancer | Renal cancer | Neuroblastoma |
| Chemotherapy regimen | Cyclophosphamide + doxorubicin | Cyclophosphamide + doxorubicin |
| Reaction onset | 1 day after cyclophosphamide (352.5 mg on days 1, 2, and 3) | 16 days after last cyclophosphamide dose (1470 mg) |
| Neurological manifestations | Transient loss of vision, retinal detachment, followed by ascites | Fits/seizures associated with elevated blood pressure (180/100 mmHg) |
| Concurrent conditions | No relevant medical history | No relevant medical history |
No relevant medical history or previous medication history was reported for either patient.
2.2 What is Posterior Reversible Encephalopathy Syndrome (PRES)?
PRES is a neurovascular clinicoradiological syndrome characterised by acute or subacute neurological manifestations that typically emerge within hours to several days. It is defined by reversible vasogenic oedema predominantly affecting the subcortical white matter of the posterior cerebral hemispheres.
2.2.1 Clinical Presentation
| Feature | Description | Prevalence in PRES |
|---|---|---|
| Seizures | Usually generalised; may be the presenting feature | Up to 92% of cases |
| Encephalopathy | Ranging from confusion and somnolence to lethargy and coma | Common |
| Headache | Often severe; may be acute or subacute | Very common |
| Visual disturbances | Blurred vision, visual field defects, cortical blindness, transient vision loss | Common (as seen in Case 1) |
| Altered mental status | Confusion, irritability, reduced consciousness | Common |
| Nausea/vomiting | Often persistent; may mimic other conditions | Common |
| Hypertension | Acute or exacerbation of pre-existing hypertension | Very common (as seen in Case 2) |
| Focal neurological deficits | Variable | Less common |
2.2.2 Pathophysiology
PRES results from endothelial dysfunction and disruption of the blood-brain barrier (BBB) , leading to vasogenic oedema. Regarding cyclophosphamide specifically, the drug can cause endothelial injury, leading to increased vascular permeability, extravasation of fluid into the brain parenchyma, and development of vasogenic oedema, particularly in posterior brain regions.
Several mechanisms contribute:
| Mechanism | Description |
|---|---|
| Endothelial injury | Direct toxic effect on vascular endothelium |
| Hypertension | Impaired cerebral autoregulation leads to hyperperfusion and fluid extravasation |
| Immunosuppressant/chemotherapy effects | Cytotoxic agents may directly disrupt BBB integrity |
| Cytokine-mediated effects | Chemotherapy may trigger inflammatory cascade affecting cerebral vessels |
| Fluid overload | Chemotherapy-related fluid shifts may contribute |
The syndrome is thought to result from a combination of hypertension, impaired cerebral autoregulation, and endothelial dysfunction. The posterior cerebral circulation, with relatively sparse sympathetic innervation, is particularly vulnerable to autoregulatory failure.
2.3 Cyclophosphamide: Pharmacological Overview
Cyclophosphamide is an alkylating prodrug that requires activation by cytochrome P450 enzymes (particularly CYP2B6) in the liver. Its active metabolites cross-link DNA, thereby inhibiting cancer cell replication and causing cell death.
2.3.1 Indications and Dosing
Cyclophosphamide is used in a wide range of hematologic and solid malignancies:
| Indication Category | Specific Indications |
|---|---|
| Hematologic malignancies | Hodgkin’s disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma, multiple myeloma, leukemias |
| Solid tumors | Neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma |
| Other | Mycosis fungoides |
Dose adjustment: When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide as well as that of the other drugs.
Neuroblastoma protocol example (OPEC protocol): Cyclophosphamide 600 mg/m² BSA IV on day 1 in combination with vincristine, cisplatin, and teniposide; repeat every 3 weeks.
2.3.2 Method of Administration
Cyclophosphamide is administered intravenously as a bolus injection or infusion, infused very slowly over 30 minutes to 2 hours. This slow infusion is essential to reduce the risk of administration rate-dependent adverse reactions (e.g., facial swelling, headache, nasal congestion, scalp burning).
2.3.3 Cyclophosphamide-Associated PRES: Plausibility and Mechanism
Cyclophosphamide has a biologically plausible association with PRES. As a cytotoxic alkylating agent, it may contribute to endothelial dysfunction and BBB disruption, especially in the presence of:
| Risk Factor | Contribution |
|---|---|
| Hypertension | Most significant risk factor; seen in Case 2 (180/100 mmHg) |
| Renal impairment | Reduced drug clearance → increased systemic exposure |
| Fluid/electrolyte imbalance | Chemotherapy-related shifts may compound endothelial injury |
| Concurrent chemotherapy | Cyclophosphamide is often combined with other neurotoxic agents (e.g., cisplatin, vincristine) |
The adverse reactions listed in the cyclophosphamide SmPC that are relevant to this case include:
| System | Adverse Reactions |
|---|---|
| Nervous system disorders | Peripheral neuropathy, polyneuropathy, neuralgia, dizziness, seizures, encephalopathy, neurotoxicity, reversible posterior leukoencephalopathy syndrome (PRES), myelopathy |
| Eye disorders | Blurred vision, visual disturbances (as seen in Case 1), conjunctivitis, eye oedema |
| Vascular disorders | Hypertension (as seen in Case 2), hypotension |
| Gastrointestinal disorders | Stomatitis, acute pancreatitis, ascites (as seen in Case 1) |
| Hepatobiliary disorders | Veno-occlusive liver disease, hepatic encephalopathy |
The presence of “reversible posterior leukoencephalopathy syndrome” explicitly listed in the SmPC product information for cyclophosphamide confirms that this association is recognised in product labelling.
2.4 PRES in Pediatric Oncology: Literature Review
Published literature supports the association between cyclophosphamide-containing chemotherapy and PRES in pediatric patients:
- A case report documented PRES in a 15-year-old boy with non-Hodgkin lymphoma receiving combination chemotherapy including cyclophosphamide, doxorubicin, vincristine, and prednisolone. The patient presented with generalised seizures and reversible blindness.
- A review of chemotherapy-induced reversible posterior leukoencephalopathy syndrome in Chinese children reported that affected patients had received chemotherapy containing cyclophosphamide, vincristine, and actinomycin-D, or therapy with cyclosporin A and glucocorticoids.
- Three children (ages 16, 12, and 12 years) suffered sudden confusional state and cortical blindness while under treatment with high-dose methotrexate, cyclophosphamide, and dactinomycin for lower limb osteosarcoma.
These cases confirm that cyclophosphamide, whether used alone or in combination regimens, can precipitate PRES in pediatric patients.
2.5 Risk Factors for PRES in Oncology Patients
In oncology patients, PRES may occur in the presence of several overlapping risk factors:
| Risk Factor Category | Specific Factors |
|---|---|
| Chemotherapy exposure | Cyclophosphamide (alkylating agent), cisplatin, methotrexate, cytarabine, gemcitabine |
| Immunosuppressive therapy | Calcineurin inhibitors (cyclosporine, tacrolimus), mTOR inhibitors |
| Hypertension | Acute or chronic; may be chemotherapy-induced or pre-existing |
| Renal impairment | Reduced drug clearance; fluid and electrolyte disturbances |
| Infection or sepsis | Inflammatory response may contribute to endothelial dysfunction |
| Fluid overload | Chemotherapy-related fluid shifts |
| Tumour-related metabolic disturbance | Hypercalcaemia, hyponatraemia, tumour lysis syndrome |
| Treatment-related electrolyte abnormalities | Especially hyponatraemia, hypomagnesaemia |
| Autoimmune disease | Underlying immune-mediated vasculopathy |
| Transplantation | Haematopoietic stem cell or solid organ transplant |
2.6 Clinical Management of Suspected PRES
2.6.1 Prevention and Early Detection
| Action | Details |
|---|---|
| Baseline assessment | Before chemotherapy: neurological status, visual complaints, blood pressure, renal and liver function, electrolytes, hydration status |
| Blood pressure monitoring | Monitor before, during, and after chemotherapy cycles. In pediatric patients, age-appropriate normative values should be used (Case 2: 180/100 mmHg in a 4.5-year-old child is markedly elevated) |
| Neurological vigilance | Pay attention to early or unexpected reactions during and after chemotherapy: seizures, visual disturbance, severe headache, persistent vomiting, irritability, confusion, altered consciousness |
| Renal function assessment | Monitor creatinine, electrolytes, fluid balance |
| Signs of tumour lysis | Monitor uric acid, LDH, potassium, phosphorus, calcium |
2.6.2 Diagnostic Approach
When PRES is suspected:
| Investigation | Role |
|---|---|
| Brain MRI | Gold standard; shows T2/FLAIR hyperintensities in posterior cerebral white matter (typically bilateral and symmetric); CT may be normal in some cases |
| Blood pressure measurement | Confirm presence of hypertension |
| Laboratory tests | Renal function, electrolytes, LFTs, CBC, inflammatory markers |
| EEG | May show seizure activity (generalised slowing, epileptiform discharges) |
| Lumbar puncture | To exclude infectious/ inflammatory causes if diagnosis uncertain |
2.6.3 Treatment Algorithm
| Priority | Intervention | Notes |
|---|---|---|
| 1. Blood pressure control | IV labetalol, nicardipine, or other antihypertensives; target gradual reduction (not >25% in first hour) | The European Heart Journal recommends immediate blood pressure reduction |
| 2. Seizure management | Benzodiazepines (lorazepam, diazepam) for acute seizures; antiepileptic drugs for persistent seizures | Status epilepticus requires emergency management |
| 3. Withdrawal of causative agents | Temporarily or permanently discontinue cyclophosphamide and other suspected agents | Do not rechallenge unless oncological benefit clearly outweighs risk |
| 4. Supportive care | Correction of electrolyte abnormalities, hydration, respiratory support if needed | |
| 5. Multidisciplinary review | Neurologist, oncologist, critical care, pharmacy | Urgent multidisciplinary assessment essential |
2.6.4 Rechallenge Decisions
Based on EPVC recommendations:
“Do not reintroduce the agent again unless the expected oncological benefit clearly outweighs the risk and enhanced monitoring/preventive measures are implemented.”
2.6.5 Reporting and Documentation
Healthcare professionals should report suspected ADRs to EPVC, including:
| Information to Include |
|---|
| Chemotherapy doses (mg/kg or mg/m²) |
| Body surface area |
| Protocol name and cycle number |
| Batch number |
| Infusion details (rate, duration, route) |
| Blood pressure trend before, during, and after infusion |
| Imaging findings (MRI/CT) |
| Laboratory results (renal function, electrolytes, LFTs) |
| Management provided |
| Dechallenge/rechallenge information |
| Outcome |
2.6.6 Chemotherapy Continuation Decision
Following PRES, chemotherapy continuation should be reassessed through a multidisciplinary benefit-risk evaluation. Options may include:
| Option | Indication |
|---|---|
| Withholding | Severe PRES with incomplete recovery |
| Delaying | Allow for clinical and radiological recovery |
| Dose reduction | If PRES was mild and dose-dependent |
| Regimen modification | Switch to alternative regimen lacking neurotoxic agents |
| Standard resumption | Only after full recovery and if alternative options are unavailable |
The decision should consider: severity of PRES, patient recovery status, cancer status, risk of recurrence, and availability of alternative treatment options.
2.7 Conclusions Regarding Causality
The cases described support a possible association between cyclophosphamide-containing chemotherapy and the development of PRES, based on:
- Temporal association (Day 1 to Day 16 post-cyclophosphamide)
- Clinical presentation consistent with PRES (seizures, visual disturbance, hypertension)
- Improvement after discontinuation of suspected medicines
- Presence of PRES in the cyclophosphamide SmPC product information
- Biologically plausible mechanism (endothelial dysfunction → BBB disruption → vasogenic oedema)
- Published case reports documenting similar associations
2.8 Recommendations for Healthcare Professionals
| Recommendation | Action |
|---|---|
| Maintain clinical suspicion | Consider PRES in adult/pediatric oncology patients receiving cyclophosphamide-containing chemotherapy who develop visual symptoms, seizures, altered mental status, persistent vomiting, headache, or hypertension |
| Perform baseline assessment | Before chemotherapy initiation, assess neurological status, visual complaints, BP, renal/liver function, electrolytes, hydration status |
| Monitor closely | During and after chemotherapy cycles, pay attention to any unusual or early reactions with other chemotherapy agents known to cause PRES |
| Act promptly when PRES is suspected | Arrange urgent multidisciplinary assessment; perform brain MRI where feasible (CT may be normal) |
| Avoid unnecessary rechallenge | Do not reintroduce the agent unless the expected oncological benefit clearly outweighs the risk and enhanced monitoring/preventive measures are implemented |
| Report suspected ADRs | Report to EPVC including chemotherapy dosing, BSA, protocol, cycle number, batch number, infusion details, BP trend, imaging findings, laboratory results, management, dechallenge/rechallenge information, and outcome |
| Review chemotherapy continuation carefully | Reassess the suspected chemotherapy regimen through a multidisciplinary benefit-risk evaluation; withholding, delaying, reducing, or modifying chemotherapy may be considered according to severity of PRES, patient recovery, cancer status, recurrence risk, and availability of alternative treatment options |
EPVC Tips – Drug Misuse as a Shared Responsibility
The EPVC newsletter emphasises that medication misuse —whether intentional or unintentional—remains a growing public health concern. It can lead to treatment failure, adverse drug events, dependency, and even death. Both healthcare professionals and the public play critical roles in minimising these risks.
1. For Healthcare Professionals
| Practice | Action |
|---|---|
| Prescribe thoughtfully | Evaluate patient history, potential for misuse, and alternative therapies before prescribing |
| Communicate clearly | Provide explicit instructions on dosage, duration, and potential side effects |
| Monitor regularly | Follow up with patients, especially when prescribing high-risk medications (opioids, sedatives, stimulants) |
| Promote safe storage and disposal | Encourage patients to keep medications secure and dispose of unused drugs properly |
| Stay informed | Keep up with guidelines on safe prescribing and emerging patterns of misuse |
2. For the Public
| Recommendation | Action |
|---|---|
| Follow directions exactly | Never take more than prescribed or use someone else’s medication |
| Ask questions | Understand why the medication is prescribed and how to take it safely |
| Avoid self-medication | Especially with antibiotics, painkillers, or sedatives |
| Store safely | Keep medications out of reach of children and others |
“Preventing drug misuse starts with awareness, communication, and responsible practices. By working together, we can ensure medications remain safe and effective tools for improving health.”
Call for ADR Reporting
1. Why Your Report Matters
The EPVC newsletter emphasises that every report counts when it comes to the safety of medicines and patients worldwide.
2. How to Report in Egypt
Healthcare professionals and patients can report adverse drug reactions to the Egyptian Drug Authority (EDA) through multiple channels:
| Method | Contact Information |
|---|---|
| pv.followup@edaegypt.gov.eg | |
| Hotline | 15301 |
| Fax | +202-23610497 |
| Address | 21 Abd El Aziz AlSoud Street, El-Manial, Cairo, Egypt, PO Box: 11451 |
| Online reporting | EDA website |
| Alternative | Report through your pharmacy, product distributor, or company hotline—they are required to forward it to EDA |
3. Additional Resources
| Resource | Access |
|---|---|
| EDA website | All medicine-related news, updates, and alerts |
| EPVC Newsletters and DHPCs | Available on EDA website |
| Alerts regarding counterfeit/falsified products | Released by Central Administration of Operations |
Clinical Takeaways and Conclusions
1. Key Messages from the April 2026 Issue
| Topic | Key Takeaway |
|---|---|
| Isotretinoin | Streamlined prescribing (removal of second prescriber requirement for under-18s) does not diminish safety obligations; Pregnancy Prevention Programme and monitoring remain mandatory. Social media-driven misuse for aesthetic purposes is dangerous and must be addressed. |
| Cyclophosphamide and PRES | Cyclophosphamide can cause PRES in pediatric oncology patients via endothelial dysfunction and BBB disruption; maintain high clinical suspicion, monitor blood pressure and neurological status, and act promptly when PRES is suspected. |
| EPVC 2026 initiatives | EPVC is actively engaging pharmacy students and professionals through academic outreach (AASTMT visit) and competitive events (VigiTest 2026) to build pharmacovigilance capacity in Egypt. |
| Drug misuse prevention | Medication misuse is a shared responsibility between healthcare professionals and the public; safe prescribing, patient education, and secure storage are essential. |
| ADR reporting | Every report counts; EPVC provides multiple accessible channels for reporting suspected ADRs. |
2. The Role of Healthcare Professionals
Healthcare professionals are the frontline of pharmacovigilance. By:
- Staying informed about safety alerts and label updates
- Educating patients about medication risks (isotretinoin teratogenicity, PRES warning signs)
- Maintaining vigilance for rare but serious adverse events
- Reporting promptly to EPVC
We collectively contribute to safer medication use for all Egyptians and patients worldwide.
References
- Egyptian Pharmacovigilance Center. EPVC Newsletter, Issue 195. Cairo: Egyptian Drug Authority; April 2026.
- Medicines and Healthcare products Regulatory Agency (UK). Isotretinoin prescribing requirements updated with revised risk-minimisation measures. London: MHRA; 22 January 2026.
- Medicines and Healthcare products Regulatory Agency (UK). Isotretinoin – changes to prescribing guidance and additional risk minimisation measures. MHRA Drug Safety Update; January 2026.
- Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). Usages détournés de l’isotrétinoïne à des fins esthétiques : l’ANSM alerte sur des risques importants. Saint-Denis: ANSM; March 2026.
- Posterior reversible encephalopathy syndrome: evolving insights in diagnosis, management, and outcomes. ScienceDirect; 2025.
- Neurotoxicity Associated with Chemotherapy. Praxis Medical Insights; 2025.
- Posterior reversible encephalopathy syndrome in non-Hodgkin’s lymphoma: Not necessarily reversible! CCIJ Online; 2015.
- Transient posterior encephalopathy induced by chemotherapy in children. Scite.ai.
- Reversible posterior leukoencephalopathy syndrome in Chinese children induced by chemotherapy: a review of five cases. Semantic Scholar; 2011.
- Commission on Human Medicines (CHM). Isotretinoin Expert Working Group review. MHRA; 2025.
- American Academy of Dermatology. Guidelines for isotretinoin dosing and post-treatment management. 2024.
- Expert Consensus on the Rational Approach to Isotretinoin Usage for Effective Management of Acne: ERAISE ACNE Recommendations. Springer Medicine; 2026.
- Posterior Reversible Encephalopathy Syndrome and Eclampsia. PMC; 2025.
- Posterior reversible encephalopathy syndrome – Knowledge @ AMBOSS. 2025.
- Treatment of Hypertension-Induced Posterior Reversible Encephalopathy Syndrome (PRES). Praxis Medical; 2025.
